Volume 66, Number 4, 2018

Pages 1309-1322
Ethics Review

Marthe Smedinga, Krista Tromp, Maartje H.N. Schermer, Edo Richard
Ethical Arguments Concerning the Use of Alzheimer’s Disease Biomarkers in Individuals with No or Mild Cognitive Impairment: A Systematic Review and Framework for Discussion
Abstract: Background: The shift to defining Alzheimer’s disease (AD) as a biological continuum, which is characterized by the presence of biomarkers instead of clinical symptoms, has sparked a widespread debate. Insight into the given arguments and their underlying moral values is crucial to ensure well-considered and appropriate AD biomarker testing in the future. Objective: To critically review the arguments in favor of or against AD biomarker testing in people with no or mild cognitive impairment and to explicate their underlying moral values. Methods: Seven databases were systematically searched for publications mentioning arguments of interest. Arguments are identified using qualitative data-analysis and evaluated within an ethical framework. Results: Our search yielded 3,657 articles of which 34 met the inclusion criteria. We discuss the clusters of arguments separate from their evaluation and the assessment of the debate as a whole. The right to know, which derives from the moral value of respect for autonomy, is a central argument in favor of biomarker testing. On the other hand, fear of the disease and lack of a disease-modifying treatment may result in a negative balance of good over inflicted harms, which argues against its use. Conclusion: Critical evaluation and weighing of the given arguments in each specific context, within an ethical framework, demonstrates the necessity to differentiate between what we hope or expect from research and where we currently stand. While AD biomarkers may have an indispensable value for research, the current advantage for clinical practice appears limited.

Pages 1323-1339

Haowei Jiang, Suman Jayadev, Michael Lardelli, Morgan Newman (Handling Associate Editor: Amalia Bruni)
A Review of the Familial Alzheimer’s Disease Locus PRESENILIN 2 and Its Relationship to PRESENILIN 1
Abstract: PRESENILIN 1 (PSEN1) and PRESENILIN 2 (PSEN2) genes are loci for mutations causing familial Alzheimer’s disease (fAD). However, the function of these genes and how they contribute to fAD pathogenesis has not been fully determined. This review provides a summary of the overlapping and independent functions of the PRESENILINS with a focus on the lesser studied PSEN2. As a core component of the γ-secretase complex, the PSEN2 protein is involved in many γ-secretase-related physiological activities, including innate immunity, Notch signaling, autophagy, and mitochondrial function. These physiological activities have all been associated with AD progression, indicating that PSEN2 plays a particular role in AD pathogenesis.

Pages 1341-1362

Arianna Menardi, Alvaro Pascual-Leone, Peter J. Fried*, Emiliano Santarnecchi* (Handling Associate Editor: Catherine Roe) *These authors contributed equally to this work.
The Role of Cognitive Reserve in Alzheimer’s Disease and Aging: A Multi-Modal Imaging Review
Abstract: Comforts in modern society have generally been associated with longer survival rates, enabling individuals to reach advanced age as never before in history. With the increase in longevity, however, the incidence of neurodegenerative diseases, especially Alzheimer’s disease, has also doubled. Nevertheless, most of the observed variance, in terms of time of clinical diagnosis and progression, often remains striking. Only recently, differences in the social, educational and occupational background of the individual, as proxies of cognitive reserve (CR), have been hypothesized to play a role in accounting for such discrepancies. CR is a well-established concept in literature; lots of studies have been conducted in trying to better understand its underlying neural substrates and associated biomarkers, resulting in an incredible amount of data being produced. Here, we aimed to summarize recent relevant published work addressing the issue, gathering evidence for the existence of a common path across research efforts that might ease future investigations by providing a general perspective on the actual state of the arts. An innovative model is hereby proposed, addressing the role of CR across structural and functional evidences, as well as the potential implementation of non-invasive brain stimulation techniques in the causal validation of such theoretical frame.

Pages 1363-1369
Short Communication

Willem S. Eikelboom, Jeroen G. J. van Rooij, Esther van den Berg, Michiel Coesmans, Lize C. Jiskoot, Ellen Singleton, Rik Ossenkoppele, John C. van Swieten, Harro Seelaar, Janne M. Papma (Handling Associate Editor: Krista Lanctôt)
Neuropsychiatric Symptoms Complicating the Diagnosis of Alzheimer’s Disease: A Case Report
Abstract: Neuropsychiatric symptoms (NPS) are increasingly recognized as a core element of Alzheimer’s disease (AD); however, clinicians still consider AD primarily as a cognitive disorder. We describe a case in which the under-recognition of NPS as part of AD resulted in substantial delay of an AD diagnosis, a wrong psychiatric diagnosis, and the organization of inappropriate care. The aim of this paper is to acknowledge NPS as an (early) manifestation of AD and to suggest features that may point toward underlying AD in older adults with late-life behavioral changes.

Pages 1371-1378
Short Communication

John C. Gant, Inga Kadish, Kuey-Chu Chen, Olivier Thibault, Eric M. Blalock, Nada M. Porter, Philip W. Landfield
Aging-Related Calcium Dysregulation in Rat Entorhinal Neurons Homologous with the Human Entorhinal Neurons in which Alzheimer’s Disease Neurofibrillary Tangles First Appear
Abstract: Aging is the leading risk factor for idiopathic Alzheimer’s disease (AD), indicating that normal aging processes promote AD and likely are present in the neurons in which AD pathogenesis originates. In AD, neurofibrillary tangles (NFTs) appear first in entorhinal cortex, implying that aging processes in entorhinal neurons promote NFT pathogenesis. Using electrophysiology and immunohistochemistry, we find pronounced aging-related Ca2+ dysregulation in rat entorhinal neurons homologous with the human neurons in which NFTs originate. Considering that humans recapitulate many aspects of animal brain aging, these results support the hypothesis that aging-related Ca2+ dysregulation occurs in human entorhinal neurons and promotes NFT pathogenesis.

Pages 1379-1387
Short Communication

Makoto Okuya*, Shinji Matsunaga*, Toshikazu Ikuta, Taro Kishi, Nakao Iwata *These authors contributed equally to this work.
Efficacy, Acceptability, and Safety of Intravenous Immunoglobulin Administration for Mild-To-Moderate Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer’s disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n=801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference=2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate AD.

Pages 1389-1395
Short Communication

Gemma Lombardi, Cristina Polito, Valentina Berti, Silvia Bagnoli, Benedetta Nacmias, Alberto Pupi, Sandro Sorbi
Contribution of Bilingualism to Cognitive Reserve of an Italian Literature Professor at High Risk for Alzheimer’s Disease
Abstract: Bilingualism is an independent component of cognitive reserve that permits to delay dementia onset up to 5 years. We describe a case of a bilingual Italian man affected by mild cognitive impairment with high cognitive reserve that, despite the presence of multiple risk factors (ApoE ε4/ε4 genotype, older age, untreated Obstructive Sleep Apnea Syndrome, AD-like biomarker alterations) did not convert to Alzheimer's disease up to 5 years follow-up. The present case confirms the role of bilingualism as a strong protective factor for dementia, even in the occurrence of multiple risk factors.

Pages 1397-1408
Patricia Llorente, Henrike Kristen, Isabel Sastre, Ana Toledano-Zaragoza, Jesús Aldudo, María Recuero, María J. Bullido
A Free Radical Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B
Abstract: Amyloid-β (Aβ), a major component of senile plaques, is generated via the proteolysis of amyloid-β protein precursor (AβPP). This cleavage also produces AβPP fragment-derived oligomers which can be highly neurotoxic. AβPP metabolism/processing is affected by many factors, one of which is oxidative stress (OS). Associated with aging, OS is an important risk factor for Alzheimer’s disease. In addition, the protein degradation systems, especially those involving cathepsins, are impaired in aging brains. Moreover, cathepsin B (CTSB) is a cysteine protease with potentially specific roles in AβPP proteolysis (β-secretase activity) and Aβ clearance (Aβ degradative activity). The present work examines the effect of OS and the involvement of CTSB in amyloid oligomer formation. The xanthine/xanthine oxidase (X-XOD) free radical generating system induced the partial inhibition of CTSB activity, which was accompanied by an increase in large amyloid oligomers. These were located throughout the cytosol and in endo-lysosomal vesicles. Cells treated with the CTSB inhibitor CA-074Me also showed increased amyloid oligomer levels, whereas those subjected to OS in the presence of the inhibitor showed no such increase. However, CTSB inhibition clearly modulated the AβPP metabolism/processing induced by X-XOD, as revealed by the increase in intracellular AβPP and secreted α-secretase-cleaved soluble AβPP. The present results suggest that CTSB participates in the changes of amyloid oligomer induced by mild OS.

Pages 1409-1424
H. Robert Brashear, Nzeera Ketter, Jennifer Bogert, Jianing Di, Stephen P. Salloway, Reisa Sperling (Handling Associate Editor: Katherine Bangen)
Clinical Evaluation of Amyloid-Related Imaging Abnormalities in Bapineuzumab Phase III Studies
Abstract: Background: Amyloid-related imaging abnormalities with effusion or edema (ARIA-E) reported in patients with mild-to-moderate Alzheimer’s disease in bapineuzumab phase III studies. Objectives: Assess symptoms, clinical severity, and ARIA-E outcomes, and to evaluate effects on cognition and function. Methods: A centralized systematic sequential locked procedure and scoring system for assessment of magnetic resonance imaging scans in 1,331 APOE ε4 noncarriers and 1,121 carriers was conducted by experienced and trained pairs of neuroradiologists. Results: Treatment-emergent ARIA-E occurred in 15.8% of bapineuzumab and 0.8% placebo-treated patients. In all treated APOE ε4 noncarriers, the percentage of patients with ARIA-E was 5.6%, 13.4%, and 19.9% in the 0.5, 1.0, and 2.0 mg/kg groups respectively, and the incidence of symptomatic ARIA-E was 1.5%, 1.5%, and 7.8%, respectively. In carriers, ARIA-E occurred in 21.2% in the 0.5 mg/kg group, and symptomatic ARIA-E occurred in 2.4%. The clinical severity of ARIA-E in those patients in whom it was detected during the study was mild in 57.1%, 61.3%, and 50.0% of cases in 0.5, 1.0, and 2.0 mg/kg noncarriers respectively, and in 73.8% of cases in 0.5 mg/kg carriers. Vascular risk factors did not appear to increase susceptibility to ARIA-E. Rate of decline in cognition and function measured by changes in ADAS-Cog/11 and DAD total scores did not meaningfully differ in patients with ARIA-E versus those without ARIA-E. Extent of cognitive decline was similar over all visit intervals. Conclusions: Overall, ARIA-E was mild and asymptomatic. ARIA-E did not demonstrate clinically meaningful acute or chronic impact on cognition or function.

Pages 1425-1435
Nancy Bartolotti, Ahmed Disouky, Arthur Kalinski, Anat Elmann, Orly Lazarov
Phytochemicals from Achillea fragrantissima are Modulators of AβPP Metabolism
Abstract: Plant derivatives offer a novel and natural source of therapeutics. The desert plant Achillea fragrantissima (Forssk) Sch. Bip (Af) is characterized by protective antioxidative and anti-inflammatory properties. Here, we examined the effect of two Af-derived phytochemicals on learning and memory, amyloid-β protein precursor (AβPP) metabolism, and tau phosphorylation in the familial Alzheimer’s disease-linked APPswe/PS1ΔE9 mouse model. We observed that mice that were injected with the phytochemicals showed a trend of improvement, albeit statistically insignificant, in the Novel Object Recognition task. However, we did not observe improvement in contextual fear conditioning, suggesting that the benefits of treatment may be either indirect or task-specific. In addition, we observed an increase in the full-length form of AβPP in the brains of mice treated with Af–derived phytochemicals. Interestingly, both in vivo and in vitro, there was no change in levels of soluble Aβ, oligomeric Aβ, or the carboxyl terminus fragments of AβPP (APP-CTFs), suggesting that the increase in full length AβPP does not exacerbate AβPP pathology, but may stabilize the full-length form of the molecule. Together, our data suggest that phytochemicals present in Af may have a modest positive impact on the progression of Alzheimer’s disease.

Pages 1437-1451
Lilian Calderón-Garcidueñas, Partha S. Mukherjee, Katharina Waniek, Max Holzer, Chih-kai Chao, Charles Thompson, Rubén Ruiz-Ramos, Ana Calderón-Garcidueñas, Maricela Franco-Lira, Rafael Reynoso-Robles, Angélica Gónzalez-Maciel, Ingolf Lachmann (Handling Associate Editor: Piotr Lewczuk)
Non-Phosphorylated Tau in Cerebrospinal Fluid is a Marker of Alzheimer’s Disease Continuum in Young Urbanites Exposed to Air Pollution
Abstract: Long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above USEPA standards is associated with Alzheimer’s disease (AD) risk. Metropolitan Mexico City (MMC) children exhibit subcortical pretangles in infancy and cortical tau pre-tangles, NFTs, and amyloid phases 1-2 by the 2nd decade. Given their AD continuum, we measured in 507 normal cerebrospinal fluid (CSF) samples (MMC 354, controls 153, 12.82±6.73 y), a high affinity monoclonal non-phosphorylated tau antibody (non-P-Tau), as a potential biomarker of AD and axonal damage. In 81 samples, we also measured total tau (T-Tau), tau phosphorylated at threonine 181 (P-Tau), amyloid-β1-42, BDNF, and vitamin D. We documented by electron microscopy myelinated axonal size and the pathology associated with combustion-derived nanoparticles (CDNPs) in anterior cingulate cortex white matter in 6 young residents (16.25±3.34 y). Non-P-Tau showed a strong increase with age significantly faster among MMC versus controls (p = 0.0055). Aβ1-42 and BDNF concentrations were lower in MMC children (p=0.002 and 0.03, respectively). Anterior cingulate cortex showed a significant decrease (p=<0.0001) in the average axonal size and CDNPs were associated with organelle pathology. Significant age increases in non-P-Tau support tau changes early in a population with axonal pathology and evolving AD hallmarks in the first two decades of life. Non-P-Tau is an early biomarker of axonal damage and potentially valuable to monitor progressive longitudinal changes along with AD multianalyte classical CSF markers. Neuroprotection of young urbanites with PM2.5 and CDNPs exposures ought to be a public health priority to halt the development of AD in the first two decades of life.

Pages 1453-1462
Zhihui Lu, Tamara B. Harris, Eric J. Shiroma, Jason Leung, Timothy Kwok
Patterns of Physical Activity and Sedentary Behavior for Older Adults with Alzheimer’s Disease, Mild Cognitive Impairment, and Cognitively Normal in Hong Kong
Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia, and mild cognitive impairment (MCI) is a transitional phase between healthy cognition and dementia. Physical activity (PA) has protective effects on cognitive decline. However, few studies have examined how PA and sedentary behavior is structured throughout the day in older adults across varied cognitive status in Hong Kong. Objective: This study aimed to compare patterns of PA and sedentary behavior among individuals with AD, MCI, or normal cognition living in Hong Kong. Methods: Participants in the MrOs and MsOs Hong Kong cohort study and the Hong Kong AD biomarker study (n=810) wore a wrist-worn accelerometer for 7 days in free-living environment. Patterns of PA in wake time and in-bed time, and detailed analysis of sedentary bouts were compared between groups using analysis of covariance adjusting for covariates. Results: Participants with MCI and low MoCA only did not differ from their cognitively normal peers in PA and sedentary behavior. Nevertheless, when comparing to the others, participants with AD exhibited significantly lower average daily counts per minute during the day (p < 0.05), and tended to start their activity later in the morning. AD participants spent a larger proportion of time in sedentary behavior (p < 0.05) and had more sedentary bouts ≥ 30 minutes (p < 0.05). Conclusions: The pattern of PA and sedentary behavior was different between individuals with AD and the others. Cognitive status may alter the purpose and type of PA intervention for AD individuals.

Pages 1463-1470
Rebecca Palm, Christian G.G. Sorg, Armin Ströbel, Debby L. Gerritsen, Bernhard Holle
Severe Agitation in Dementia: An Explorative Secondary Data Analysis on the Prevalence and Associated Factors in Nursing Home Residents
Abstract: Background: The phenomena of severe agitation is not well understood and often not adequately treated. Objective: This article determines the prevalence and associated factors of severe agitation in nursing home residents with dementia. Methods: Secondary data analysis within an observational study in German nursing homes with n = 1,967 participants. We assessed severity of agitation with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and defined the construct of agitation as a composite score of the NPI-Q items agitation/aggression, disinhibition, and irritability/lability; the dependent variable of severe agitation was considered as being present in residents who scored ‘severe’ in at least one of these symptoms. A binary logistic regression model was calculated to estimate associations. Results: The prevalence of severe agitation was 6.3% (n = 124). The strongest associations were found for elation/euphoria (OR 7.6, CI 3.1 – 18.5), delusions (OR 7.3, CI 4.0 – 13.2), apathy/indifference (OR 2.8, CI 1.7 – 4.7), anxiety (OR 2.2, CI 1.2 – 3.8), nighttime behaviors (OR 2.4, CI 1.4 – 4.2), motor disturbances (OR 2.4, CI 1.4 – 4.1), and male sex (OR 2.4. CI 1.3 – 4.2). Conclusion: Severe agitation in nursing home residents with dementia is a relevant clinical issue as approximately 70% of residents have a dementia. Residents with elation/euphoria and delusions may have a stronger risk of showing severe agitation. We consider delusions as a possible cause of agitation and therefore a prelude to agitation. Although it might be possible that elation/euphoria follows from agitation, we hypothesize that the residents first experience elation/ euphoria and exhibit agitation afterwards.

Pages 1471-1481
Ilaria Bacigalupo, Flavia Mayer, Eleonora Lacorte, Alessandra Di Pucchio, Fabrizio Marzolini, Marco Canevelli, Teresa Di Fiandra, Nicola Vanacore (Handling Associate Editor: Amalia C. Bruni)
A Systematic Review and Meta-Analysis on the Prevalence of Dementia in Europe: Estimates from the Highest-Quality Studies Adopting the DSM IV Diagnostic Criteria
Abstract: Background: Dementia, including Alzheimer’s disease (AD), is one of the most burdensome medical conditions. Usually, the reviews that aim at calculating the prevalence of dementia include estimates from studies without assessing their methodological quality. Alzheimer’s Disease International (ADI) proposed a score to assess the methodological quality of population-based studies aimed at estimating the prevalence of dementia. During the last three years, the European Commission has funded three projects (Eurodem, EuroCoDe, and ALCOVE) in order to estimate the prevalence of dementia in Europe. Objective: The aim of this study was to perform a systematic review and meta-analysis of data on the prevalence of dementia in Europe derived from studies that included only subjects with a diagnosis of dementia according to the DSM IV criteria, and that had a high quality score according to ADI criteria. Methods: We considered the studies selected by the two projects EuroCoDe (1993-2007) and Alcove (2008-2011), and we performed a new bibliographic search. For the systematic review, we only selected the subset of articles that included subjects with a diagnosis of dementia according to the DSM IV criteria. The studies were qualitatively assessed using the ADI tool. Results: The meta-analysis considered 9 studies that were carried out in Europe between 1993 and 2018 including a total of 18,263 participants, of which 2,137 were diagnosed with dementia. The prevalence rate standardized for age and sex resulted 7.1%. Discussion: This is the first systematic review on the prevalence of dementia in Europe considering only high-quality studies adopting the same diagnostic criteria (i.e., DSM IV).

Pages 1483-1495
Giovana Silva Leandro, Adriane Feijó Evangelista, Romulo Rebouças Lobo, Danilo Jordão Xavier, Julio César Moriguti, Elza Tiemi Sakamoto-Hojo
Changes in Expression Profiles Revealed by Transcriptomic Analysis in Peripheral Blood Mononuclear Cells of Alzheimer’s Disease Patients
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative pathology associated with accumulation of DNA damage. Inflammation and cell cycle alterations seem to be implicated in the pathogenesis of AD, although the molecular mechanisms have not been thoroughly elucidated to date. The aim of the present study was to evaluate whether peripheral blood mononuclear cells (PBMCs) of AD patients display alterations in gene expression profiles, focusing on finding markers that might improve the diagnosis of AD. Blood samples were collected from 22 AD patients and 13 healthy individuals to perform genome-wide mRNA expression. We found 593 differentially expressed genes in AD compared to controls, from which 428 were upregulated, and 165 were downregulated. By performing a gene set enrichment analysis, we observed pathways involved in inflammation, DNA damage response, cell cycle, and neuronal processes. Moreover, functional annotation analyses indicated that differentially expressed genes are strongly related to pathways associated with the cell cycle and the immune system. The results were compared with those of an independent study on hippocampus samples, and a number of genes in common between both studies were identified as potential peripheral biomarkers for AD, including DUSP1, FOS, SLC7A2, RGS1, GFAP, CCL2, ANGPTL4, and SSPN. Taken together, our results demonstrate that PBMCs of AD patients do present alterations in gene expression profiles, and these results are comparable to those previously reported in the literature for AD neurons, supporting the hypothesis that blood peripheral mononuclear cells express molecular changes that occur in the neurons of AD patients.

Pages 1497-1506
Claire Sulmont-Rossé, Marie Gaillet, Carine Raclot, Michel Duclos, Maud Servelle, Stéphanie Chambaron
Impact of Olfactory Priming on Food Intake in an Alzheimer’s Disease Unit
Abstract: Alzheimer’s disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents' needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on subsequent food intake and eating behavior. Thirty-two residents (> 75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident’s interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real-life setting.

Pages 1507-1517
Tzeyu L. Michaud, Mohammad Siahpush, Paraskevi A. Farazi, Jungyoon Kim, Fang Yu, Dejun Su, Daniel L. Murman (Handling Associate Editor: Yorghos Tripodis)
The Association between Body Mass Index, and Cognitive, Functional, and Behavioral Declines for Incident Dementia
Abstract: Background: Association between high adiposity and the clinical progression of dementia remains puzzling. Objective: To separately examine the association between body mass index (BMI) and cognitive, functional, and behavioral declines before, at, and after diagnosis of dementia, and further stratified by age groups, and sex. Methods: A total of 1,141 individuals with incident dementia were identified from the Uniform Data Set of the National Alzheimer’s Coordinating Center. Cognitive function was evaluated by Mini-Mental State Exam, functional abilities were assessed using Functional Activities Questionnaire, and behavioral symptoms were captured by Neuropsychiatric Inventory Questionnaire at each follow-up visit. We used separate linear-mixed effects models to examine the association. Results: Compared to moderate baseline BMI, high baseline BMI was associated with 0.30-point slower annual progression rates in functional decline. For individuals aged 76 and over, high baseline BMI was associated with 0.42-point faster progression rates in cognitive decline annually. A U-shaped association between baseline BMI and cognitive decline was observed among men. Conclusion: BMI levels before dementia diagnosis may facilitate the identification of different risk profiles for progression rates of cognitive and functional declines in individuals who developed dementia.

Pages 1519-1528
Angel Piriz, Dolly Reyes, Atul Narkhede, Vanessa A. Guzman, Fawad Viqar, Irene B. Meier, Mariana Budge, Pedro Mena, Stephen Dashnaw, Joseph Lee, Christiane Reitz, Jose Gutierrez, Luis Campos, Martin Medrano, Rafael Lantigua, Richard Mayeux, Adam M. Brickman (Handling Associate Editor: Rhoda Au)
Cerebrovascular Disease and Neurodegeneration in Alzheimer’s Disease with and without a Strong Family History: A Pilot Magnetic Resonance Imaging Study in Dominican Republic
Abstract: The incidence and prevalence of Alzheimer’s disease (AD) dementia are higher among Caribbean Hispanics than among non-Hispanic Whites. The causes of this health disparity remain elusive, partially because of the relative limited capacity for biomedical research in the developing countries that comprise Caribbean Latin America. To begin to address this issue, we were awarded a Development Research Award from the US NIH and Fogarty International Center in order to establish the local capacity to integrate magnetic resonance imaging (MRI) into studies of cognitive aging and dementia in Dominican Republic, establish collaborations with Dominican investigators, and conduct a pilot study on the role of cerebrovascular markers in the clinical expression of AD. Ninety older adult participants with and without AD dementia and with and without a strong family history of AD dementia received MRI scans and clinical evaluation. We quantified markers of cerebrovascular disease (white matter hyperintensities [WMH], presence of infarct, and presence of microbleed) and neurodegeneration (entorhinal cortex volume) and compared them across groups. Patients with AD dementia had smaller entorhinal cortex and greater WMH volumes compared with controls, regardless of family history status. This study provides evidence for the capacity to conduct MRI studies of cognitive aging and dementia in Dominican Republic. The results are consistent with the hypothesis that small vessel cerebrovascular disease represents a core feature of AD dementia, as affected participants had elevated WMH volumes irrespective of family history status.

Pages 1529-1537
Susanne Angermann*, Johannes Schier*, Marcus Baumann, Dominik Steubl, Christine Hauser, Georg Lorenz, Roman Günthner, Matthias C. Braunisch, Stephan Kemmner, Robin Satanovskij, Bernhard Haller, Uwe Heemann, Timo Grimmer, Thomas Lehnert, Richard Bieber, Martin Pachmann, Jürgen Braun, Julia Scherf, Gabriele Schätzle, Michael Fischereder, Timo Grimmer*, Christoph Schmaderer *These authors contributed equally to this work.
Cognitive Impairment Is associated with Mortality in Hemodialysis Patients
Abstract: Background: The prevalence of cognitive impairment in hemodialysis patients is notably high. In previous studies performed in the general population, cognitive impairment has been associated with increased mortality. Objective: We evaluated the relationship between global cognitive function tested by a short screening instrument and mortality in hemodialysis patients. Methods: Cognitive testing was performed in 242 maintenance hemodialysis patients under standardized conditions at baseline using the Montreal Cognitive Assessment (MoCA). Cognitive impairment was defined as a MoCA test score ≤ 24 points, as published previously. All-cause mortality was monitored during a median follow-up of 3.54 years. Kaplan-Meier plot and Cox regression model adjusted for known risk factors for mortality in hemodialysis patients were used to examine a possible association between global cognitive function and all-cause mortality. Results: A MoCA test score ≤ 24 points resulted in a significant almost 3-fold higher hazard for all-cause mortality (unadjusted hazard ratio [HR]: 2.812; 95% confidence interval [95% CI]: 1.683–4.698; p < 0.001). After adjustment, this association was attenuated but remained significant (adjusted HR: 1.749; 95% CI: 1.007–3.038; p = 0.047). Conclusion: Impairment of global cognitive function measured by a short screening instrument was identified for the first time as an independent predictor of all-cause mortality in hemodialysis patients. Thus, implementing the MoCA test in clinical routine could contribute to a better risk stratification of this patient population.

Pages 1539-1548
Jose A. Soria, Branko N. Huisa, Steven D. Edland, Irene Litvan, Guerry M. Peavy, David P. Salmon, Lawrence A. Hansen, Douglas R. Galasko, James B. Brewer, Hector M. González, Robert A. Rissman
Clinical-Neuropathological Correlations of Alzheimer’s Disease and Related Dementias in Latino Volunteers
Abstract: Clinical, neuropsychological, and neurological procedures used to diagnose Alzheimer’s disease (AD) and related dementias were largely developed and validated in well-educated, non-Latino, English-speaking populations. Sociocultural and genetic differences in Latinos might influence the accuracy of clinical diagnosis of AD and other dementias. We aim to compare the accuracy of the clinical diagnosis of AD and related dementias in Latinos with the corresponding neuropathological diagnosis. From the UCSD Alzheimer’s Disease Research Center longitudinal cohort, we selected all Latino participants who had autopsy neuropathological studies from 1991 to 2017. Participants underwent annual neurological clinical evaluations, standard neuropsychological tests, neuroimaging, and genotyping of Apolipoprotein E. We calculated the sensitivity and specificity of the clinical diagnosis of AD against the primary pathological diagnosis. Of the 34 participants with a primary neuropathological diagnosis of AD, 33 (97.1%) were correctly clinically diagnosed as having AD at the last clinical evaluation, and 1 was incorrectly diagnosed with dementia with Lewy bodies. Of the 19 participants without a primary neuropathological diagnosis of AD, 8 were incorrectly clinically diagnosed with probable AD at the last clinic evaluation. The clinical diagnosis of AD at the last clinical evaluation had 97.1% sensitivity and 57.9% specificity for autopsy-verified AD. In this Latino cohort, clinicians predicted AD pathological findings with high sensitivity but moderate specificity. Tangle-only dementia was the most common misdiagnosis. Our study suggests that current procedures and instruments to clinically determine AD in Latinos have high sensitivity compared with neuropathology, but specificity needs to be improved.

Pages 1549-1558
Margaret E. Flanagan, Brenna Cholerton, Caitlin S. Latimer, Laura S. Hemmy, Steven D. Edland, Kathleen S. Montine, Lon R. White, Thomas J. Montine (Handling Associate Editor: Peter Nelson)
TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study
Abstract: Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p<0.0001, 95% CI 3.57–34.13). In the NS, there were significant associations between TDP-43 and HS (OR=16.44, p>0.001 95%, CI 7.10–38.00) and Alzheimer’s disease (AD) severity (OR=1.74, p=0.009, 95% CI 1.15–2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR= 2.11, p=0.022, 95% CI 1.11–4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p= 0.005, 95% CI 1.22–3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p<0.001, 95% CI 1.58–3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

Pages 1559-1576
Yan-Chun Xie, Zhao-Hui Yao, Xiao-Li Yao, Jianzhen Pan, Shao-Feng Zhang, Yong Zhang, Jichang Hu (Handling Associate Editor: Ling-Qiang Zhu)
Glucagon-Like Peptide-2 Receptor Is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion
Abstract: Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

Pages 1577-1585
Leandro Boson Gambogi, Henrique Cerqueira Guimarães, Leonardo Cruz de Souza, Paulo Caramelli (Handling Associate Editor: Michael Hornberger)
Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample
Abstract: Background: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. Objectives: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. Methods: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. Results: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. Conclusions: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features.

Pages 1587-1597
Erin L. Boespflug, Matthew J. Simon, Emmalyn Leonard, Marjorie Grafe, Randall Woltjer, Lisa C. Silbert, Jeffrey A. Kaye, Jeffrey J. Iliff (Handling Associate Editor: Asa Hatami)
Targeted Assessment of Enlargement of the Perivascular Space in Alzheimer’s Disease and Vascular Dementia Subtypes Implicates Astroglial Involvement Specific to Alzheimer’s Disease
Abstract: Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer’s disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS.

Pages 1599-1608
Yat-Fung Shea, Warren Barker, Maria T. Greig-Gusto, David A. Loewenstein, Steven T. DeKosky, Ranjan Duara
Utility of Amyloid PET Scans in the Evaluation of Patients Presenting with Diverse Cognitive Complaints
Abstract: Background: The impact of amyloid positron emission tomography (Aβ-PET) in a “real-world” memory disorders clinic remains poorly studied. Objective: we studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. Methods: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer’s Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans. Results: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer’s disease (26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen’s kappa of 0.23 (95% CI 0-0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p=0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p<0.001), management (84.2% versus 40%, p<0.01) and discussion of results and advice on lifestyles (73.7% versus 22.9%, p<0.001). Conclusions: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans.

Pages 1609-1617
Jochen René Thyrian, Bernhard Michalowsky, Johannes Hertel, Markus Wübbeler, Johannes Gräske, Bernhard Holle, Susanne Schäfer-Walkmann, Karin Wolf-Ostermann, Wolfgang Hoffmann
How Does Utilization of Health Care Services Change in Ceople with Dementia Served by Dementia Care Networks? Results of the Longitudinal, Observational DemNet-D-Study
Abstract: Background: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN. Objective: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time. Methods: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points over a period of one year. Data was assessed via semi-structured interviews at the participants’ homes. Results: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR=1.32; 95%-CI: 1.08-1.63) or occupational therapy (OR=1.24; 95%-CI: 1.02-1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR=0.57; 95%-CI: 0.37-0.87) and increased the chances to utilize no services (OR=2.08; 95%-CI: 1.29-3.33). Conclusion: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation.

Pages 1619-1633
Ross Penninkilampi, Anne-Nicole Casey, Maria Fiatarone Singh, Henry Brodaty
The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis
Abstract: It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 – May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR=1.59, 95% CI 1.31-1.96; I2=0.00%) and poor social support (RR=1.28, 95% CI 1.01-1.62; I2=55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR=0.88, 95% CI 0.80-0.96; I2=0.00%). Loneliness was associated with non-significantly increased risk (RR=1.38, 95% CI 0.98-1.94; I2=45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention.

Pages 1635-1644
Paul T. Francis, Helen Costello, Gillian M. Hayes (Handling Associate Editor: Colin Masters)
Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value
Abstract: Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that ‘big data’, readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia.

Pages 1645-1655
Ben Chen, Xiaomei Zhong, Naikeng Mai, Qi Peng, Min Zhang, Xinru Chen, Zhangying Wu, Laiquan Zou, Wanyuan Liang, Cong Ouyang, Yujie Wu, Yuping Ning
Interactive Effect of Depression and Cognitive Impairment on Olfactory Identification in Elderly People
Abstract: Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p<0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p<0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression.

Pages 1657-1682
Tauqeerunnisa Syeda, Mónica Sanchez-Tapia, Laura Pinedo-Vargas, Omar Granados, Daniel Cuervo-Zanatta, Eleazar Rojas-Santiago, Sofía Díaz-Cintra, Nimbe Torres, Claudia Perez-Cruz (Handling Associate Editor: Benedict Albensi)
Bioactive Food Abates Metabolic and Synaptic Alterations by Modulation of Gut Microbiota in a Mouse Model of Alzheimer’s Disease
Abstract: Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer’s disease (AD). GM modulates a host’s health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β. GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM’s composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function.

Pages 1683-1694
Marcos Zanco, Jessica Plácido, Valeska Marinho, José Vinicius Ferreira, Felipe Oliveira, Renato Sobral Monteiro-Junior, Maria Lage Barca, Knut Engedal, Jerson Laks, Andrea Deslandes (Handling Associate Editor: Gilles Chopard)
Spatial Navigation in the Elderly with Alzheimer’s Disease: A Cross-Sectional Study
Abstract: Background: Spatial navigation is a fundamental cognitive ability that allows an individual to maintain independence by facilitating the safe movement from one place to another. It emerges as one of the first deficits in patients with Alzheimer's disease (AD). Objective: To compare spatial navigation performance in the healthy elderly and AD patients through use of the Floor Maze Test (FMT)—an easy-to-apply two-dimensional (2D) maze—and determine which cognitive and functional capacities were associated with performance in this task. Methods: The FMT was administered to 24 AD patients and 36 healthy controls. Spatial navigation was evaluated through the FMT. Functional capacity was evaluated through the Senior Fitness Test battery of tests. Cognitive functions were evaluated through the Mini-Mental State Examination (MMSE), verbal fluency, digit span test, and the Rey Auditory Verbal Learning Test (RAVLT). Results: The group with AD was significantly slower and presented more errors at all stages of the FMT. Planning Time (PT) performance was associated with cardiorespiratory resistance (Step test) and delayed memory according to the RAVLT (R2=0.395, p<0.001). Performance in the Immediate Maze Time (IMT) and Delayed Maze Time (DMT) was associated with global cognitive status (MMSE) (R2=0.509) and delayed memory (R2=0.540). Conclusion: Patients with AD present significant spatial navigation deficits. Their performance on the FMT is influenced by cardiorespiratory capacity, memory, and global cognitive function. As exercise helps to improve executive function and functional capacity, future intervention studies should be carried out to analyze the possible effects of physical exercise on spatial navigation.

Pages 1695-1704
Jianlan Gu*, Feng Chen*, Dandan Chu, Ying Lu, Khalid Iqbal, Cheng-Xin Gong, Fei Liu *These authors contributed equally to this work.
Rbfox3/NeuN Regulates Alternative Splicing of Tau Exon 10
Abstract: Alternative splicing of tau exon 10 generates tau isoforms with three or four microtubule-binding repeats, 3R-tau or 4R-tau, which are under developmental regulation. Dysregulation of tau exon 10 splicing is sufficient to cause neurodegenerative disorders. The RNA-binding Fox3 (Rbfox3), identified as NeuN, regulates RNA processing. However, whether Rbfox3/NeuN regulates tau exon 10 splicing is unknown. In the present study, we found that the developmental expression of 4R-tau coincided with the expression of Rbfox3 in rat brains. Rbfox3 enhanced tau exon 10 inclusion. Tau intron 10 contains UGCAUG, the conservative binding sequence of Rbfox3. Intron 10 of tau pre-mRNA was co-immunoprecipitated by Rbfox3/NeuN. Deletion mutants of the RNA recognition motif (RRM) or three RNA-binding sites of the RRM in Rbfox3/NeuN failed to enhance tau exon 10 inclusion. Rbfox3ΔE8, specifically expressed in the fetal brain, did not affect tau exon 10 splicing. The level of Rbfox3/NeuN was reduced and was associated with the ratio of 4R-tau/3R-tau in the excitotoxic mouse brains induced by kainic acid. These findings suggest that Rbfox3/NeuN regulates the alternative splicing of tau exon 10 and that decreased Rbfox3/NeuN may lower the ratio of 4R-tau/3R-tau.

Pages 1705-1720
Seiko Goto, Xuting Shen, Minkai Sun, Yutaka Hamano, Karl Herrup
The Positive Effects of Viewing Gardens for Persons with Dementia
Abstract: Dementia is highly prevalent among the worldwide elderly population. Only a small number of the currently marketed drugs are effective in controlling its symptoms, and none has any effect on its progression. Further, as the condition advances, even these pharmaceuticals lose their efficiency, and new research into interventions that might improve the life quality of patients at the end stage of dementia and their families is increasingly rare. In our previous studies, we explored the benefits of exposure to nature, in the form of Japanese garden, for persons with advanced dementia. In the current work, we extended our observations to two new locations and a new set of subjects with a different ethnic composition with the goal of identifying interventions that might improve their quality of life. We found that, even in these new settings, garden observation not only relieved physiological stress, it improved qualitative measures such as verbalization and memory retrieval. We present data that viewing the garden is a holistic experience rather a solely visual stimulus. Our new data further support the conclusion that garden observation is worth including in the care planning schedule of advanced dementia patients. Its low cost and easy availability make it an economical adjunct to current pharmacological methods that has the potential to improve the quality of life of people with dementia.

Pages 1721-1730
Hojin Choi, Jee Hyang Jeong, Yong Bum Kim, Kwang Deog Jo, Jin-Yong Choi, Kyung-Hun Kang, Heeyoung Kang, Do-Young Kwon, Bong-Goo Yoo, Hyun Jin Lee, Byoung-Soo Shin, Sung-Man Jeon, Oh Dae Kwon, Jin-Suk Kim, Soo-Joo Lee, Hyun Jeong Han, Youngsoo Kim, Tai-Hwan Park, Young Jin Kim, Mee Young Park, Hui-Jun Yang, Hyun-Young Park, Hae-Eun Shin, Jung Seok Lee, YoungSoon Yang, Yo Han Jung, Ae Young Lee, Dong-Ick Shin, Kyong Jin Shin, Kee Hyung Park (Handling Associate Editor: Sang Won Seo)
Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer’s Disease
Abstract: Background: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer’s disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. Methods: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. Results: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. Conclusion: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients’ functional status.

Pages 1731-1743
ShuJuan Fan, XiaoHui Xian*, Li Li*, XiaoGuang Yao, YuYan Hu, Min Zhang, WenBin Li (Handling Associate Editor: Jianzhi Wang) *These authors contributed equally to this work.
Ceftriaxone Improves Cognitive Function and Upregulates GLT-1-Related Glutamate-Glutamine Cycle in APP/PS1 Mice
Abstract: Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle.

Pages 1745-1752
Larissa Lahme*, Eliane Esser*, Natasa Mihailovic, Friederike Schubert, Jost Lauermann, Andreas Johnen, Nicole Eter, Thomas Duning*, Maged Alnawaiseh* *These authors contributed equally to this work.
Evaluation of Ocular Perfusion in Alzheimer's Disease Using Optical Coherence Tomography Angiography
Abstract: Background: There is increasing evidence for the involvement of cerebrovascular factors in Alzheimer's disease (AD). Objective: To evaluate retinal and optic nerve head perfusion in patients with AD using optical coherence tomography angiography (OCTA), and to analyze the correlations of quantitative OCTA metrics with AD pathology and vascular cerebral lesions in AD patients. Methods: 36 eyes of 36 patients with AD (study group) and 38 eyes of 38 healthy subjects (control group) were prospectively included in this study. OCTA was performed using RTVue XR Avanti with AngioVue. In addition, patients underwent a detailed ophthalmological and neurological examination including Mini-Mental State Examination, cerebral magnetic resonance imaging, and amyloid-β (Aβ) and tau levels in the cerebrospinal fluid (CSF). Results: The flow density in the superficial retinal OCT angiogram of the macula in the study group was significantly lower compared to the control group (p=0.001). There was a significant correlation between the flow density in the superficial retinal OCT angiogram of the macula, as measured using OCTA, and the Fazekas scale (Spearman’s correlation coefficient = -0.520; p=0.003). There was no significant correlation between the Aβ or tau levels in the CSF and the flow density data. Conclusion: Patients with AD showed a reduced flow density in the radial peripapillary capillaries layer and in the superficial retinal OCT angiogram when compared with healthy controls. The reduced retinal flow density measured using OCTA is not specifically associated with AD pathology but is associated with the vascular cerebral lesions in AD.