Volume 75, Number 4, IN PRESS

Review
Joachim Enengl, Michael R. Hamblin, Peter Dungel (Handling Associate Editor: Jessica Peter)
Photobiomodulation for Alzheimer’s Disease: Translating Basic Research to Clinical Application
Abstract: One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory research and medical practitioners who are not exposed to highly specialized journals. This review covers the literature on photobiomodulation therapy as a novel approach to prevent and treat Alzheimer’s disease, aiming to bridge that gap by gathering together the terms and technical specifications into a single concise suggestion for a treatment protocol. In light of the predicted doubling in the number of people affected by dementia and Alzheimer’s disease within the next 30 years, a treatment option which has already shown promising results in cell culture studies and animal models, and whose safety has already been proven in humans, must not be left in the dark. This review covers the mechanistic action of photobiomodulation therapy against Alzheimer’s disease at a cellular level. Safe and effective doses have been found in animal models, and the first human case studies have provided reasons to undertake large-scale clinical trials. A brief discussion of the minimally effective and maximum tolerated dose concludes this review, and provides the basis for a successful translation from bench to bedside.

Review
Gianmarco Rosa, Chiara Giannotti, Lucia Martella, Federico Massa, Gianluca Serafini, Matteo Pardini, Flavio Mariano Nobili, Fiammetta Monacelli, for the Disease Management Team on Dementia of the IRCCS Ospedale Policlinico San Martino (Genoa, I) (Handling Associate Editor: Patricia Mecocci)
Brain Aging, Cardiovascular Diseases, Mixed Dementia, and Frailty in the Oldest Old: From Brain Phenotype to Clinical Expression
Abstract: Dementia is an age-related clinical condition, with higher incidence rates in older ages. However, there is some evidence that a reverse epidemiology is also observed. Namely, the cohort analysis of dementia incidence rates by birth in selected populations demonstrated a decreased incidence of dementia in late life across the last twenty years, possibly due to decreased incidence of cardiovascular disorders and increased education and cognitive reserve. In line with that, age is probably a proxy for other pathophysiological processes rather than a strictly causative factor for the onset of dementia, especially in oldest old persons. The present narrative review provides an update on the clinical interplay between the spectrum of brain aging, cardiovascular morbidity, dementia pathologies, and their clinical expression in the oldest old patients. Available evidence suggests that vascular prevention in the perspective of dementia largely involve middle ages, with an apparent reverse epidemiology in oldest old. Similarly, the present findings underline how cognitive resilience and frailty may be key relevant mediators in the modulation of the clinical expression of brain mixed neuropathologies in persons over 85 years old, providing a new integrated conceptual framework.

Review
Claude Robert, Concepción S. Wilson, Richard B. Lipton, Charles-Daniel Arreto
Evolution of the Research Literature and the Scientific Community of Alzheimer’s Disease from 1983-2017: A 35-Year Survey
Abstract: This study surveys the development of Alzheimer’s disease (AD) in the research literature, the scientific community, and the journals containing AD papers over a 35-year period. Research papers on AD published from 1983 to 2017 in journals indexed in the Web of Science were analyzed in seven five-year periods. The number of AD papers increased from 1,095 in 1983-1987 to 50,532 by 2013-2017 and in the same time period, the number of participating countries went from 27 to 152. The US was the most prolific country throughout, followed by several European countries, Canada, Australia, and Japan. Asian countries have emerged and by 2013-2017, China surpassed all but the US in productivity. Countries in Latin America and Africa have also contributed to AD research. Additionally, several new non-governmental institutions (e.g., ADNI, ADI) have emerged and now play a key role in the fight against AD. Likewise the AD scientific publishing universe evolved in various aspects: an increase in number of journals containing AD papers (227 journals in 1983-1987 to 3,257 in 2013-2017); appearance of several AD-focused journals, e.g., Alzheimer’s & Dementia, Journal of Alzheimer’s Disease; and the development of special issues dedicated to AD. Our paper complements the numerous extant papers on theoretical and clinical aspects of AD and provides a description of the research landscape of the countries and journals contributing papers related to AD.

Short Communication
André Hajek, Hans-Helmut König
Fear of Dementia in the General Population: Findings from the German Socio-Economic Panel (GSOEP)
Abstract: The aim was to identify the determinants of fear of dementia in the general population. Data were taken from the innovation sample (n=1,498; year 2012) of a nationally representative, longitudinal study. Summarizing, 28.8% reported no fear of dementia, 34.3% reported a little fear of dementia, 21.2% reported some fear of dementia, and 15.7% reported severe fear of dementia. Regressions showed that increased fear of dementia was associated with increased age, being female, an increased perceived own risk for developing dementia, an increased agreement that a diagnosis of dementia would ruin one’s life, and a decreased perception that memory degradation is preventable. Addressing modifiable factors may assist in reducing fear of dementia.

Rezaul K. Khandker, Craig W. Ritchie, Christopher M. Black, Robert Wood, Eddie Jones, Xiaohan Hu, Baishali M. Ambegaonkar
Multi-National, Cross-Sectional Survey of Healthcare Resource Utilization in Patients with All Stages of Cognitive Impairment, Analyzed by Disease Severity, Country, and Geographical Region
Abstract: Background: Alzheimer’s disease (AD) is one of the most disabling conditions worldwide and the disease burden increases with the aging global population. There are only a few prospective studies using real-world data to support effective healthcare resource utilization (HCRU) in AD. Objective: To confirm the association between HCRU and AD severity in a real-world population, including patients with all cognitive impairment (CI) severities. Methods: Data were drawn from a multi-national, cross-sectional survey of physicians and their consulted patients with all stages (very mild, mild, moderate, and severe) of CI including AD conducted in France, Germany, Italy, Spain, UK, US, and Canada. Elements of HCRU including medical consultations, professional caregiver hours, hospitalization, and institutionalization were compared between CI severity subgroups, and by country and region. Results: 6,143 CI patients were included with very mild (n=659), mild (n=2,473), moderate (n=2,603), and severe (n=408) dementia. HCRU increased with increasing CI severity (p<0.001) for the majority of elements measured. Further analyses of overall and regional populations also confirmed significant increases in most HCRU elements with increasing disease severity. The general trend toward increased HCRU with increased CI severity was also seen in individual countries. Individual country data appeared to indicate that earlier intervention decreased hospitalizations and full-time institutionalization at the later (more severe) disease stages. Conclusion: Our findings confirmed that HCRU increases with increasing CI severity. Effective intervention in early disease could therefore reduce or delay incurring greater HCRU costs associated with more severe disease. Further studies are needed to confirm this hypothesis.

Pan Wang, Bo Zhou, Hongxiang Yao, Sangma Xie, Feng Feng, Zengqiang Zhang, Yan’e Guo, Ningyu An, Yuying Zhou, Xi Zhang, Yong Liu (Handling Associate Editor: Jin-Tai Yu)
Aberrant Hippocampal Functional Connectivity Is Associated with Fornix White Matter Integrity in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in older individuals, and amnestic mild cognitive impairment (aMCI) is currently considered the prodromal stage of AD. The hippocampus and fornix interact functionally and structurally, with the fornix being the major efferent white matter tract from the hippocampus. Objective: The main aim of this study was to examine the impairments present in subjects with AD or aMCI and the relationship of these impairments with the microstructure of the fornix and the functional connectivity (FC) and gray matter volume of the hippocampus. Methods: Forty-four AD, 34 aMCI, and 41 age- and gender-matched normal controls (NCs) underwent neuropsychological assessments and multimode MRI. We chose the bilateral hippocampi as the region of interest in which gray matter alterations and FC with the whole brain were assessed and the fornix body as the region of interest in which the microstructural integrity of the white matter was observed. We also evaluated the relationship among gray matter alterations, the abnormal FC of the hippocampus and the integrity of the fornix in AD/aMCI. Results: Compared to the NC group, the AD and aMCI groups demonstrated decreased gray matter volume, reduced FC between the bilateral hippocampi and several brain regions in the default mode network and control network, and damaged integrity of the fornix body (decreased fractional anisotropy and increased diffusivity). We also found that left hippocampal FC with some regions, the integrity of the fornix body, and cognition ability were significantly correlated. Therefore, our findings suggest that damage to white matter integrity may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. Conclusion: AD and aMCI are diseases of disconnectivity including not only functional but also structural disconnectivity. Damage to white matter integrity may partially explain the reduced resting-state FC in AD and aMCI. These findings have significant implications for diagnostics and modeling and provide insights for understanding the disconnection syndrome in AD.

Owen A. Williams, Yang An, Nicole M. Armstrong, Melissa Kitner-Triolo, Luigi Ferrucci, Susan M. Resnick
Profiles of Cognitive Change in Preclinical and Prodromal Alzheimer’s Disease Using Change-Point Analysis
Abstract: Background: Alzheimer’s disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. Objective: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. Methods: 165 older adults (baseline age range: 61.1-91.2) from the Baltimore Longitudinal Study of Aging developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Results: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making A test before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Conclusion: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Ivan C. Zibrandtsen, Mikkel Agger, Troels W. Kjaer (Handling Associate Editor: Amy Clements-Cortes)
Gamma Entrainment in a Large Retrospective Cohort: Implications for Photic Stimulation Therapy for Alzheimer’s Disease
Abstract: Background: Studies on mice models of Alzheimer’s disease (AD) have suggested potential therapeutic benefits of intermittent photic stimulation at 40 Hz. Objective: We examined the physiological response of 40 Hz intermittent photic stimulation (IPS) on routine EEG in a large retrospective cohort to investigate the effects of age on induced gamma oscillations by intermittent photic stimulation. Since most AD patients are elderly, it is important for future research to know if age affects photic stimulation. Methods: Retrospective data from 1,464 subjects aged 0-91. We performed frequency analysis and automatic peak detection and used regression analysis to investigate the effects of age and sex on peak frequencies and amplitude changes. To investigate the spread of the induced gamma oscillations, we assessed averaged topographies of 40 Hz band power. Results: There was a statistically significant but very minor effect of age on amplitude change (-0.002 normalized power per year, p < 0.0001) but not for sex (p = 0.728). Detection probability of induced peaks was significantly predicted by both age (OR = 0.988, CI 95 % [0.984, 0.993], p<0.00001) and sex (OR = 0.625, CI 95 % [0.496, 0.787], p<0.0001). The induced 40 Hz gamma entrainment is spatially confined to the occipital area. Conclusion: There is a significant effect of age on induced gamma activity, but advanced age does not fundamentally change the behavior of the response in either magnitude or spatial distribution. This fact is important regarding future research into the possible therapeutic effects of photic stimulation in patients with AD.

Ferdinando Petrazzuoli, Susanna Vestberg, Patrik Midlöv, Hans Thulesius, Erik Stomrud, Sebastian Palmqvist
Brief Cognitive Tests Used in Primary Care Cannot Accurately Differentiate Mild Cognitive Impairment from Subjective Cognitive Decline
Abstract: Background: Differentiating mild cognitive impairment (MCI) from subjective cognitive decline (SCD) is important because of the higher progression rate to dementia for MCI and when considering future disease-modifying drugs that will have treatment indications at the MCI stage. Objective: We examined if the two most widely-used cognitive tests, the Mini-Mental State Examination (MMSE) and clock-drawing test (CDT), and a test of attention/executive function (AQT) accurately can differentiate MCI from SCD. Methods: We included 466 consecutively recruited non-demented patients with cognitive complaints from the BioFINDER study who had been referred to memory clinics, predominantly from primary care. They were classified as MCI (n=258) or SCD (n=208) after thorough neuropsychological assessments. The accuracy of MMSE, CDT, and AQT for identifying MCI was examined both in training and validation samples and in the whole population. Results: As a single test, MMSE had the highest accuracy (sensitivity 73%, specificity 60%). The best combination of two tests was MMSE 91 seconds (sensitivity 56%, specificity 78%), but in logistic regression models, their AUC (0.76) was not significantly better than MMSE alone (AUC 0.75). CDT and AQT performed significantly worse (AUC 0.71; p<0.001–0.05); otherwise no differences were seen between any combination of two or three tests. Conclusion: Neither single nor combinations of tests could differentiate MCI from SCD with adequately high accuracy. There is a great need to further develop, validate, and implement accurate screening-tests for primary care to improve accurate identification of MCI among individuals that seek medical care due to cognitive symptoms.

Guanqun Chen*, Chunhua Liu*, Kun Yang, Yuxia Li, Can Sheng, Yunyan Xie, Xiaochen Hu, Jiehui Jiang, Ying Han (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Beneficial Effects of Brain Reserve on Cognition in Subjective Cognitive Decline from the SILCODE Study
Abstract: Background: Clinical research has demonstrated that brain reserve (BR) could exert positive effects on cognition for patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, the effects of BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To examine cross-sectional effects of BR on cognition in SCD populations. Methods: One hundred forty-nine subjects were studied from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Head circumference was used as a proxy of BR. Cognition was assessed across four domains (memory, executive, language, and general cognitive functions). Multiple linear regression models were conducted to examine effects of BR on cognitive scores. Furthermore, we addressed the question that whether the degree of self-perception of cognitive decline modified the effect of BR on cognitive performance in SCD subjects. Results: We found a positive effect of BR on language cognition in subjects with SCD. Furthermore, the positive effect of BR on language cognition survived in SCD participants with a low degree of self-perception of cognitive decline while disappeared in SCD participants with a high degree of self-perception of cognitive decline. Conclusion: This study suggests that BR has the potential to delay or slow down cognitive decline in SCD individuals, especially for mild SCD.

Anna McKeever*, Alvar F. Paris*, James Cullen, Lawrence Hayes, Craig W. Ritchie, Karen Ritchie, Adam D. Waldman, Katie Wells, Albert Busza, Isabelle Carriere, John T. O'Brien**, Li Su** *,**These authors contributed equally to this work.
Hippocampal Subfield Volumes in Middle-Aged Adults at Risk of Dementia
Abstract: Background: Alzheimer’s disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention. Objective: We aimed to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia. Methods: We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40-59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI images taken at baseline and 2-year follow-up. Results: FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up. Conclusion: CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis.

Víctor Andrade, Nicole Cortés, Gabriela Pastor, Andrea Gonzalez, Nicolás Ramos-Escobar, Edgar Pastene, Leonel E. Rojo, Ricardo B. Maccioni
N-Acetyl Cysteine and Catechin-Derived Polyphenols: A Path Toward Multi-Target Compounds Against Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to “damage signals”. The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection. Objective: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives. Methods: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC. Results: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway. Conclusion: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro.

Lei Yu, Gary Mottola, David A. Bennett, Patricia A. Boyle
Confidence in Financial and Health Literacy and Cognitive Health in Older Persons
Abstract: Background: Financial and health literacy are associated with cognitive outcomes in old age. However, the extent to which confidence in financial and health literacy is related to cognitive health is unknown. Objective: This study tests the hypothesis that confidence is associated with cognitive outcomes above and beyond actual financial and health literacy. Methods: A total of 974 older adults underwent assessments of literacy and confidence in literacy, and were subsequently followed for annual clinical evaluations. Financial and health literacy were assessed via a series of items which were immediately followed by questions asking participants to rate their confidence in accuracy of their response to the literacy items. Cox proportional hazards models examined the associations of financial and health literacy and confidence in literacy with incident Alzheimer’s disease (AD); and linear mixed models examined the associations with cognitive decline. Results: Participants on average were 81.2 years of age at literacy assessment. Over up to 9 years of annual follow-up, 175 (18%) developed AD. After adjusting for demographics, higher confidence in financial literacy was associated with lower risk of AD and slower decline in cognition. The results persisted after further adjusting for financial literacy performance. Similar findings were observed for confidence in health literacy. Further, older adults who expressed under-confidence relative to their actual level of financial and health literacy were more likely to develop AD and experienced faster cognitive decline. Conclusion: Both domain-specific literacy and confidence in one’s financial and health knowledge are important determinants of cognitive health among community-dwelling older adults.

Jose A. Luchsinger, Priya Palta, Brady Rippon, Greysi Sherwood, Luisa Soto, Fernando Ceballos, Krystal Laing, Kay Igwe, Hengda He, Qolamreza Razlighi, Jeanne Teresi, Herman Moreno, Adam M. Brickman
Pre-Diabetes, but not Type 2 Diabetes, Is Related to Brain Amyloid in Late Middle-Age
Abstract: Background: Type 2 diabetes is a dementia risk factor, but its relation to Alzheimer’s disease (AD), the most common cause of dementia, is unclear. Objective: Our primary objective was to examine the association of pre-diabetes and type 2 diabetes with brain amyloid-β (Aβ), the putative main culprit of AD. Our secondary objective was to examine the association of pre-diabetes and type 2 diabetes with neurodegeneration, cerebrovascular disease (CVD), and memory performance. Methods: We conducted a cross-sectional study of 350 late middle-aged Hispanics without dementia in New York City. We classified diabetes status as normal glucose tolerance (NGT), pre-diabetes, and type 2 diabetes following American Diabetes Association Criteria. Brain Aβ was ascertained as global Aβ standardized value uptake ratio using PET with 18F-Florbetaben. Neurodegeneration was operationalized as cortical thickness in regions affected by AD using MRI. CVD was operationalized as white matter hyperintensity volume (WMH) on MRI, and memory as performance with the selective reminding test (SRT). Results: Mean age was 64.15 ± 3.34 years, 72.00% were women, and 35.43% were APOE ε4 carriers. Pre-diabetes, but not type 2 diabetes, was associated with higher Aβ compared with NGT. Type 2 diabetes treatment was related to lower Aβ. Type 2 diabetes was related to lower cortical thickness, higher WMH, and lower SRT score. Conclusion: Pre-diabetes, but not type 2 diabetes, is associated with higher brain Aβ in late middle age, and this observation could be explained by the relation of diabetes treatment with lower brain Aβ. Whether type 2 diabetes treatment lowers brain Aβ requires further study.

Fabrizio Vecchio, Francesca Miraglia, Francesca Alù, Matteo Menna, Elda Judica, Maria Cotelli, Paolo Maria Rossini
Classification of Alzheimer’s Disease with Respect to Physiological Aging with Innovative EEG Biomarkers in a Machine Learning Implementation
Abstract: Background: Several studies investigated clinical and instrumental differences to make diagnosis of dementia in general and in Alzheimer’s disease (AD) in particular with the aim to classify, at the individual level, AD patients and healthy controls cooperating with neuropsychological tests for an early diagnosis. Advanced network analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity and could be used in classification processes. If successfully reached, this goal would add a low-cost, easily accessible, and non-invasive technique with neuropsychological tests. Objective: To investigate the possibility to automatically classify physiological versus pathological aging from cortical sources’ connectivity based on a support vector machine (SVM) applied to EEG small-world parameter. Methods: A total of 295 subjects were recruited: 120 healthy volunteers and 175 AD. Graph theory functions were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA. A machine-learning classifier (SVM) was applied. EEG frequency bands were: delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). Results: The receiver operating characteristic curve showed AUC of 0.97±0.03 (indicating very high classification accuracy). The classifier showed 95%±5% sensitivity, 96%±3% specificity, and 95%±3% accuracy for the classification. Conclusion: EEG connectivity analysis via a combination of source/connectivity biomarkers, highly correlating with neuropsychological AD diagnosis, could represent a promising tool in identification of AD patients. This approach represents a low-cost and non-invasive method, one that utilizes widely available techniques which, when combined, reach high sensitivity/specificity and optimal classification accuracy on an individual basis (0.97 of AUC).

Edwin C.K. Tan, Duangjai Lexomboon, Henrike Häbel, Johan Fastbom, Maria Eriksdotter, Kristina Johnell, Gunilla Sandborgh-Englund
Xerogenic Medications as a Predictor for Dental Health Intervention in People with Dementia
Abstract: Background: Older adults with dementia often have poor oral health. Chronic use of xerogenic medications may contribute to adverse dental outcomes. Objective: To investigate the impact of xerogenic medication classes on the predicted risk for dental interventions in people with dementia. Methods: This was a population-based cohort study involving 30,955 individuals registered in the Swedish Dementia Registry (SveDem) from 2008 to 2012. Data were linked with other national registers. The exposure was xerogenic medication classes used in the three years prior to dementia diagnosis (baseline). The primary outcome was the composite of number of tooth extractions and dental restorations over the three-year follow-up period. Secondary outcomes included the number of tooth extractions and number of dental restorations. Poisson regression models were used to estimate the association between the exposure and outcomes. Analyses were adjusted for age, gender, Mini-Mental State Examination, living arrangement, dementia disorder, average number of medications, Charlson’s comorbidity index, number of dental visits, and number of teeth. Results: After adjusting for potential covariates, the use of urological drugs (incidence rate ratio [IRR] 1.16, 95% CI 1.04–1.28), proton pump inhibitors (IRR 1.13, 95% CI 1.04–1.23), and opioids (IRR 1.19, 95% CI 1.06–1.34) were significantly associated with the primary composite outcome. Conclusion: The use of specific classes of xerogenic medications was associated with an increased risk for tooth extractions and restorations in people with dementia. The risks and benefits of xerogenic medications, in the context of oral health, should be carefully assessed in this vulnerable population.

Aki Kawasaki, Sami Ouanes, Sylvain V. Crippa, Julius Popp (Handling Associate Editor: Cecilia Lee)
Early-Stage Alzheimer’s Disease Does Not Alter Pupil Responses to Colored Light Stimuli
Abstract: Background: Pathologic changes in cerebral and retinal structures governing the pupillary light reflex occur in Alzheimer’s disease (AD). Analysis of pupillary responses originating from different retinal cells may allow for non-invasive detection of cerebral AD pathology. Objective: This study aimed to quantify the pupil light reflex using a portable chromatic pupillometer in patients with early stage AD and compare their responses to those of a healthy control group. Methods: Participants in this case-control pilot study were recruited from a well-characterized cohort of elderly people participating in a larger prospective study on early AD. Cognitive testing, volumetric brain imaging, and lumbar puncture were performed in all participants to define two groups: early AD, i.e., cognitively impaired subjects with biomarker-confirmed AD pathology, and control group of subjects with normal cognition and normal CSF biomarker profile. Pupil responses to red and blue light stimuli intended to activate cone photoreceptors and melanopsin ganglion cells were recorded under photopic conditions. Results: Sixteen patients with AD (mean age 77 years) and sixteen controls (mean age 71 years) were tested. Baseline pupil size was significantly smaller in AD patients. Pupillary contraction amplitude to all red and blue lights was also smaller in AD patients but did not reach statistical significance. The post-illumination pupillary response was the same between the two groups. Conclusion: Compared to healthy controls, we found only a smaller resting size of the pupil in patients with early AD. The pupillary dynamics to light stimulation remained relatively preserved.

Claire Gueib, Alina Pop, Aurélie Bannay, Emeline Nassau, Reinhard Fescharek, Roger Gil, Amandine Luc, Thérèse Rivasseau Jonveaux
Impact of a Healing Garden on Self-Consciousness in Patients with Advanced Alzheimer’s Disease: An Exploratory Study
Abstract: Background: The environment of patients with Alzheimer’s disease and related disorders (ADRD) intensifies the consequences of cognitive impairment and exacerbates behavioral problems if inappropriate or, conversely, mitigate these problems if its design is tailored to the needs of these persons. Objective: We evaluate the impacts of hospitalization and of a specific healing garden on self-consciousness which represent a central impairment in ADRD. The self-consciousness questionnaire (SCQ), validated for its assessment at mild to moderate phases of the disease, explores the dimensions of personal identity, awareness of cognitive deficiencies, self-assessment of affective state, awareness of body representation, prospective memory, capacity for introspection, and moral judgments. Methods: After having verified, by means of a preliminary study, its feasibility to the more advanced stages of the disease, this questionnaire allowed assessment of the impact of the environment by comparing, in routine care, patients hospitalized in a cognitive-behavioral unit who solely remain indoors with others who use the Art, Memory and Life healing garden. Results: A significant decrease in SCQ due to an increase in anosognosia during hospitalization was observed in the group that remained indoors. For the group using the garden, a positive effect on overall SCQ score was observed, as a result of a significant improvement in body representation as the driving parameter. Conclusion: Factors that are grounded in the hypotheses that spearheaded its conception, such as sensory enrichment, familiarity, contact with nature, scaffolding role for cognitive functions, supportive effect for social interactions, and the “Nancy hypotheses of beauty”, thus contribute to their validation.

Surya Prakash Rai⁠⁠, Markus Krohn, ⁠Jens Pahnke
Early Cognitive Training Rescues Remote Spatial Memory but Reduces Cognitive Flexibility in Alzheimer’s Disease Mice
Abstract: Background: Spatial memory dysfunction has been demonstrated in mouse models of Alzheimer’s disease (AD) which is consistent with the clinical finding that the early signature of AD includes difficulties in the formation and/or storage of a memory. A stored memory—a long term memory—can be modulated via process called as memory retrieval that can either lead toward memory reconsolidation or even memory extinction. Objective: We aim to shed light on the fate of the spatial memory during memory reactivation and memory extinction using a water maze task. Methods: In Set-up I, we trained 3-month-old mice (wild-type mice and mice with cerebral β-amyloidosis) and assessed the fate of remote memory after four months of retention interval (RI). In Set-up II, we performed an early-extensive training at 2 months of age, retrained the same mice at 3 months of age, introduced four months of RI, and finally assessed remote spatial memory at 7 months of age. Results: We find in β-amyloidosis mice that memory reactivation problems were detectable at 7 months of age and were alleviated by cognitive overtraining. Similarly, forgetting of remote spatial memory was also minimized by cognitive overtraining. Finally, we show that the cognitive training facilitates the recovery of the reactivated spatial memory while reducing the ability to form new spatial memory in AD mice. Conclusion: This result may explain the rationality behind the cognitive reserve observed in AD patients and elderly with severe β-amyloidosis not corresponding to the actual low dementia symptoms.

Keith W. VanDusen, Sarada Eleswarpu, Eugene W. Moretti, Michael J. Devinney, Donna M. Crabtree, Daniel T. Laskowitz, Marty G. Woldorff, Kenneth C. Roberts, John Whittle, Jeffrey N. Browndyke, Mary Cooter, Frank W. Rockhold, Oke Anakwenze, Michael P. Bolognesi, Mark E. Easley, Michael N. Ferrandino, William A. Jiranek, Miles Berger, for the MARBLE Study Investigators (Handling Associate Editor: Catherine Price)
The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction
Abstract: Background: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer’s disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. Objective: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age ≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. Methods: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive drug or placebo before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. Conclusion: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

Pierre Courault, Stéphane Emery, Sandrine Bouvard, François Liger, Fabien Chauveau, David Meyronet, Anthony Fourier, Thierry Billard, Luc Zimmer, Sophie Lancelot
Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer’s Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P
Abstract: Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer’s disease (AD) and associated disorders. Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages. Methods: Patients were classified according to the “ABC” NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n=8) and severe AD (“High”; n=8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n=15), “Low” (n=18), “Int” (n=20), and “High” (n=15). Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between “High” and HC groups. In vitro quantitative autoradiography showed a significant difference between the “High” and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined (“Low”, “Intermediate”, and “High”) (p = 0.011). Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.

Ranran Zhou, Wen Hu, Chun-Ling Dai, Cheng-Xin Gong, Khalid Iqbal, Dalong Zhu, Fei Liu
Expression of Microtubule Associated Protein Tau in Mouse Pancreatic Islets Is Restricted to Autonomic Nerve Fibers
Abstract: Background: Evidence from clinical studies and basic research has shown a strong correlation between Alzheimer’s disease (AD) and type 2 diabetes. Tau, a neuronal microtubule-associated protein, is hyperphosphorylated and aggregated into neurofibrillary tangles in the AD brain. However, the expression of tau in pancreas is under debate. Objective: We determined the expression of tau in mouse pancreas. Methods: We used western blots, immunoprecipitation, and immunohistochemical staining to analyzed pancreatic expression of tau in mice. Results: We found that neither total tau nor phosphorylated tau was detectable in the mouse pancreas by western blots. Immunostaining with pan tau antibodies R134d and Tau-5 revealed bright and dense varicosities in the pancreatic islets and the exocrine pancreas. These varicosities were immunoreactive to synapsin 1, a presynaptic marker which can outline autonomic nerve profiles in pancreas, exhibiting complete colocalization with tau. Importantly, endocrine cells in islets did not exhibit specific immunoreactivity to any of pan tau antibodies tested, nor did the exocrine cells. Conclusion: In the mouse pancreas, we found that tau is exclusively expressed in autonomic nerve fibers, but there is no detectable expression in endocrine cells in the islet.

Anne Cristine Guevarra*, Sheng Chun Ng*, Seyed Ehsan Saffari, Benjamin Yi Xin Wong, Russell Jude Chander, Kok Pin Ng, Nagaendran Kandiah (Handling Associate Editor: Matthew Pase) *These authors contributed equally to this work.
Age Moderates Associations of Hypertension, White Matter Hyperintensities, and Cognition
Abstract: Background: Hypertension and white matter hyperintensities (WMH) are mutually associated risk factors for cognitive impairment. However, age may modify the associations between hypertension and WMH, and their links to cognitive impairment. Objective: We evaluated the interaction between age and hypertension on WMH, and the age-stratified associations of hypertension and WMH with cognition. Methods: Key measures include systolic blood pressure (SBP), WMH (modified Fazekas visual ratings of cranial MRI), and the Montreal Cognitive Assessment (MoCA). Participants (N=488) with prodromal and mild dementia were age-stratified (≤49, 50–59, 60–69, ≥70), and considered hypertensive if their SBP≥140 mmHg. The interaction between age strata and hypertension on WMH, and age-stratified associations of hypertension and WMH with cognition, were evaluated using multiple linear regression analyses. Analyses controlled for other risk factors for WMH and cognitive impairment. Results: Age moderated the association between SBP and WMH. Hypertension was associated with higher WMH only in those aged 60–69, and WMH trends across age bands differed between those with and without hypertension. Finally, WMH and SBP≥140 were independently associated with lower MoCA scores within the 50–59 age band, while WMH alone was associated with poorer MoCA scores in the ≥70 age band. Conclusion: In adults with prodromal or mild dementia, hypertension was associated with WMH specifically in the 60-69 age strata. Associations between hypertension and WMH with poorer cognition also differed across age bands. Future studies will be needed to investigate whether blood pressure management to slow cognitive decline by targeting WMH may be age dependent.

Ursula Haditsch, Theresa Roth, Leo Rodriguez, Sandy Hancock, Thomas Cecere, Mai Nguyen, Shirin Arastu-Kapur, Sean Broce, Debasish Raha, Casey C. Lynch, Leslie J. Holsinger, Stephen S. Dominy, Florian Ermini
Alzheimer’s Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active Gingipains
Abstract: Background: Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer’s disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported. Objective: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h. Methods: Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA. Results: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased. Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.

Yanli Jiang, Longfei Li, Chun-Ling Dai, Ranran Zhou, Cheng-Xin Gong, Khalid Iqbal, Jin-Hua Gu, Fei Liu (Handling Associate Editor: Jianzhi Wang)
Effect of Peripheral Insulin Administration on Phosphorylation of Tau in the Brain
Abstract: Background: Abnormally hyperphosphorylated tau is the major protein of neurofibrillary tangles in Alzheimer’s disease. Insulin activates PI3K-AKT signaling and regulates tau phosphorylation. Impaired brain insulin signaling is involved in Alzheimer’s disease pathogenesis. However, the effect of peripheral insulin on tau phosphorylation is controversial. Objective: In the present study, we determined the effect of peripheral insulin administration on tau phosphorylation in brain. Methods: We intraperitoneally injected a super physiological dose of insulin to mice and analyzed PI3K-AKT signaling and tau phosphorylation in brains by western blots. Results: We found that peripherally administered insulin activated the PI3K-AKT signaling pathway immediately in the liver, but not in the brain. Tau phosphorylation in the mouse brain was found to be first decreased (15 min) and then increased (30 min and 60 min) after peripheral insulin administration and these changes correlated inversely with body temperature and the level of brain protein O-GlcNAcylation. Maintaining body temperature of mice post peripheral insulin administration prevented the insulin/hypoglycemia-induced tau hyperphosphorylation after peripheral insulin administration. Conclusion: These findings suggest that peripheral insulin can induce tau hyperphosphorylation through both hypothermia and downregulation of brain protein O-GlcNAcylation during hypoglycemia.

Rachel Fremont, Masood Manoochehri, Nicole M. Armstrong, Venkata S. Mattay, Jose A. Apud, Mary C. Tierney, D. P. Devanand, Yunglin Gazes, Christian Habeck, Eric Wassermann, Jordan Grafman, Edward D. Huey
Tolcapone Treatment for Cognitive and Behavioral Symptoms in Behavioral Variant Frontotemporal Dementia: A Placebo-Controlled Crossover Study
Abstract: Background: There are currently no disease-targeted treatments for cognitive or behavioral symptoms in patients with behavioral variant frontotemporal dementia (bvFTD). Objective: To determine the effect of tolcapone, a specific inhibitor of Catechol-O-Methyltransferase (COMT), in patients with bvFTD. Methods: In this randomized, double-blind, placebo-controlled, cross-over study at two study sites, we examined the effect of tolcapone on 28 adult outpatients with bvFTD. The primary outcome was reaction time on the N-back cognitive test. As an imaging outcome, we examined differences in the resting blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal intensity between subjects on placebo versus tolcapone performing the N-back test. Secondary outcomes included measures of cognitive performance and behavioral disturbance using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Neuropsychiatric Inventory-Questionnaire (NPI-Q), and Clinical Global Impressions scale (CGI). Results: Tolcapone was well tolerated and no patients dropped out. The most frequent treatment-related adverse event during tolcapone treatment was elevated liver enzymes (21%). There were no significant differences between tolcapone treatment and placebo in the primary or imaging outcomes. However, there were significant differences between RBANS total scores (p<0.01), NPI-Q total scores (p=0.04), and CGI total scores (p=0.035) between treatment conditions which were driven by differences between baseline and tolcapone conditions. Further, there was a trend toward significance between tolcapone and placebo on the CGI (p=0.078). Conclusions: Further study of COMT inhibition and related approaches with longer duration of treatment and larger sample sizes in frontotemporal lobar degeneration-spectrum disorders may be warranted.

Jinshil Hyun, Charles B. Hall, Martin J. Sliwinski, Mindy J. Katz, Cuiling Wang, Ali Ezzati, Richard B. Lipton (Handling Associate Editor: Ozioma Okonkwo)
Effect of Mentally Challenging Occupations on Incident Dementia Differs Between African Americans and Non-Hispanic Whites
Abstract: Background: Engaging in mentally challenging activities may protect against dementia in late life. However, little is known whether the association between mentally challenging activities and dementia risk varies with race/ethnicity. Objective: The current study investigates whether having jobs with higher mental stimulation is differentially associated with a decreased risk of dementia between African Americans (AAs) and non-Hispanic Whites (nHWs). Methods: The sample consisted of 1,079 individuals (66% nHWs, 28% AAs; age=78.6±5.3) from the longitudinal Einstein Aging Study. Occupation information of each participant was collected retrospectively at baseline and was linked to the substantive complexity of work score from the Dictionary of Occupational Titles. Cox proportional hazards models were used to evaluate the associations of occupational complexity with risk of dementia. Results: Individuals whose jobs had moderate-to-high levels of complexity, compared to those with the lowest complexity, were at modestly decreased risk for incident dementia. When stratified by race, moderate-to-high levels of occupational complexity were significantly associated with lower risk of developing dementia for AAs (HR=0.35). When risk of dementia was evaluated based on the combinations of race × occupational complexity, AAs with lowest occupational complexity showed the highest risk of developing dementia, while other combinations exhibited lower risk of developing dementia (HRs=0.36~0.43). Conclusion: Our results suggest that moderate-to-high levels of complexity at work are associated with a decreased risk of incident dementia in AAs. Understanding the differential effects of mentally challenging occupations across race/ethnicity may suggest important intervention strategies that could mitigate racial disparities in dementia rates.

Barbara Kramarz, Rachael P. Huntley, Milagros Rodríguez-López, Paola Roncaglia, Shirin C.C. Saverimuttu, Helen Parkinson, Rina Bandopadhyay, Maria-Jesus Martin, Sandra Orchard, Nigel M. Hooper, David Brough, Ruth C. Lovering
Gene Ontology Curation of Neuroinflammation Biology Improves the Interpretation of Alzheimer’s Disease Gene Expression Data
Abstract: Background: Gene Ontology (GO) is a major bioinformatic resource used for analysis of large biomedical datasets, for example from genome-wide association studies, applied universally across biological fields, including Alzheimer’s disease (AD) research. Objective: We aim to demonstrate the applicability of GO for interpretation of AD datasets to improve the understanding of the underlying molecular disease mechanisms, including the involvement of inflammatory pathways and dysregulated microRNAs (miRs). Methods: We have undertaken a systematic full article GO annotation approach focused on microglial proteins implicated in AD and the miRs regulating their expression. PANTHER was used for enrichment analysis of previously published AD data. Cytoscape was used for visualizing and analyzing miR-target interactions captured from published experimental evidence. Results: We contributed 3,084 new annotations for 494 entities, i.e., on average six new annotations per entity. This included a total of 1,352 annotations for 40 prioritized microglial proteins implicated in AD and 66 miRs regulating their expression, yielding an average of twelve annotations per prioritized entity. The updated GO resource was then used to re-analyze previously published data. The re-analysis showed novel processes associated with AD-related genes, not identified in the original study, such as ‘gliogenesis’, ‘regulation of neuron projection development’, or ‘response to cytokine’, demonstrating enhanced applicability of GO for neuroscience research. Conclusions: This study highlights ongoing development of the neurobiological aspects of GO and demonstrates the value of biocuration activities in the area, thus helping to delineate the molecular bases of AD to aid the development of diagnostic tools and treatments.

Rebecca E. Amariglio, Rachel F. Buckley, Jennifer S. Rabin, Kathryn V. Papp, Yakeel T. Quiroz, Elizabeth C. Mormino, Kathryn P. Sparks, Keith A. Johnson, Dorene M. Rentz, Reisa A. Sperling
Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study
Abstract: Background: Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer’s disease pathological differences. Objective: To examine potential differences in cross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline. Methods: 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Results: Lower levels of educational attainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educational factors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β = -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β = -0.055, p = 0.025) after adjusting for covariates. Conclusion: Accounting for educational factors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.