Volume 83, Number 2, IN PRESS

Review
Saravanan Subramaniam, David T. Blake, Christos Constantinidis *These authors contributed equally to this work.
Cholinergic Deep Brain Stimulation for Memory and Cognitive Disorders
Abstract: Memory and cognitive impairment as sequelae of neurodegeneration in Alzheimer’s disease and age-related dementia are major health issues with increasing social and economic burden. Deep brain stimulation (DBS) has emerged as a potential treatment to slow or halt progression of the disease state. The selection of stimulation target is critical, and structures that have been targeted for memory and cognitive enhancement include the Papez circuit, structures projecting to the frontal lobe such as the ventral internal capsule, and the cholinergic forebrain. Recent human clinical and animal model results imply that DBS of the nucleus basalis of Meynert can induce a therapeutic modulation of neuronal activity. Benefits include enhanced activity across the cortical mantle, and potential for amelioration of neuropathological mechanisms associated with Alzheimer’s disease. The choice of stimulation parameters is also critical. High-frequency, continuous stimulation is used for movement disorders as a way of inhibiting their output; however, no overexcitation has been hypothesized in Alzheimer’s disease and lower stimulation frequency or intermittent patterns of stimulation (periods of stimulation interleaved with periods of no stimulation) are likely to be more effective for stimulation of the cholinergic forebrain. Efficacy and long-term tolerance in human patients remain open questions, though the cumulative experience gained by DBS for movement disorders provides assurance for the safety of the procedure.

Review
Alison M. Luckey, Ian H. Robertson, Brian Lawlor, Anusha Mohan, Sven Vanneste
Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer’s Disease in Females
Abstract: This article aims to reevaluate our approach to female vulnerability to Alzheimer’s disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ε4 polymorphism (APOE ε4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.

Hypothesis
Avantika Samkaria, Khushboo Punjabi, Shallu Sharma, Shallu Joon, Kanika Sandal, Tirthankar Dasgupta, Pooja Sharma, Pravat K. Mandal
Brain Stress Mapping in COVID-19 Survivors Using MR Spectroscopy: New Avenue of Mental Health Status Monitoring
Abstract: Coronavirus (COVID-19) has emerged as a human catastrophe worldwide, and it has impacted human life more detrimentally than the combined effect of World Wars I and II. Various research studies reported that the disease is not confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus is potent to affect the central nervous system (CNS). Moreover, the damage to CNS may continue to rise even after the COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment. Neuroimaging techniques provide the ability to detect and quantify pathological manifestations in the brain of COVID-19 survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-19 on the mental health of the survivors. Extensive research is required in this direction for identifying the mechanism and implications of COVID-19 in the brain. Additionally, longitudinal follow-up studies are also needed to perform for monitoring the effects of this pandemic on individuals over a prolonged period.

Short Communication
Michitaka Funayama, Asuka Nakajima , Shin Kurose, Taketo Takata
Putative Alcohol-Related Dementia as an Early Manifestation of Right Temporal Variant of Frontotemporal Dementia
Abstract: Diagnosis of frontotemporal dementia is challenging in the early stages. Various psychiatric and neurological diseases are misdiagnosed as frontotemporal dementia and vice versa. Here we present a case with right temporal variant of frontotemporal dementia who presented with alcohol dependency and remarkable behavioral symptoms and was first misdiagnosed as having alcohol-related dementia. He then revealed symptoms related to right temporal variant of frontotemporal dementia, such as prosopagnosia, difficulty recognizing his housemates, loss of empathy, ritualistic behaviors, and difficulty finding and comprehending words. Retrospectively, his alcohol dependency itself was considered an early manifestation of right temporal variant of frontotemporal dementia.

Short Communication
Jasmine Cárcamo, Anton J Kociolek, Kayri K Fernández, Yian Gu, Carolyn W Zhu, Yaakov Stern, Stephanie Cosentino (Handling Associate Editor: Melissa Lamar)
Neuropsychological Predictors of Severe Functional Dependency in a Multiethnic Community Cohort of Individuals with Alzheimer’s Disease
Abstract: To assess the predictive value of neuropsychological tests for severe dependency in Alzheimer’s disease as defined by the Equivalent Institutional Care Rating Scale, in a multiethnic, community cohort. The sample included 146 elders from the Predictors 3 cohort. Cox proportional hazard models tested the predictive value of each neuropsychological test at baseline on relative risk of meeting severe dependency. Higher semantic Processing and Memory test scores at baseline were associated with lower risk of meeting severe dependency in the adjusted Cox models. The integrity of semantic processing and memory abilities in dementia appears to predict time to severe functional dependency.

Mincheol Park, Kyoungwon Baik, Young-gun Lee, Sung Woo Kang, Jin Ho Jung, Seong Ho Jeong, Phil Hyu Lee, Young H. Sohn, Byoung Seok Ye
Implication of Small Vessel Disease MRI Markers in Alzheimer’s Disease and Lewy Body Disease
Abstract: Background: Small vessel disease (SVD) magnetic resonance imaging (MRI) markers including deep and periventricular white matter hyperintensities (PWMH), lacunes, and microbleeds are frequently observed in Alzheimer's disease (AD) and Lewy body disease (LBD), but their implication has not been clearly elucidated. Objective: To investigate the implication of SVD MRI markers in cognitively impaired patients with AD and/or LBD. Method: We consecutively recruited 57 patients with pure AD-related cognitive impairment (ADCI), 49 with pure LBD-related cognitive impairment (LBCI), 45 with mixed ADCI/LBCI, and 34 controls. All participants underwent neuropsychological tests, brain MRI, and amyloid positron emission tomography. SVD MRI markers including the severity of deep and PWMH and the number of lacunes and microbleeds were visually rated. The relationships among vascular risk factors, SVD MRI markers, ADCI, LBCI, and cognitive scores were investigated after controlling for appropriate covariates. Results: LBCI was associated with more severe PWMH, which was conversely associated with an increased risk of LBCI independently of vascular risk factors and ADCI. PWMH was associated with attention and visuospatial dysfunction independently of vascular risk factors, ADCI, and LBCI. Both ADCI and LBCI were associated with more lobar microbleeds, but not with deep microbleeds. Conclusion: Our findings suggest that PWMH could reflect degenerative process related with LBD, and both AD and LBD independently increase lobar microbleeds.

Xuhao Zhao, Eddie Jun Yi Chong, Wei Qi, Ting Pang, Xin Xu, Christopher Chen
Domain-Specific Cognitive Trajectories Among Patients with Minor Stroke or Transient Ischemic Attack in a 6-Year Prospective Asian Cohort: Serial Patterns and Indicators
Abstract: Background: Long-term post-stroke cognitive impairment (PSCI) has often been overlooked, especially among patients with minor stroke or transient ischemic attack (TIA). Objective: To assess 6-year domain-specific cognitive trajectories among survivors of minor stroke or TIA and to identify possible indicators associated with cognitive trajectories, as well as long-term and incident PSCI. Methods: Eligible participants completed cognitive and clinical assessments at baseline (2 weeks after stroke) and up to 5 follow-up visits in 6 years. Mixed linear models and generalized estimating equations were adopted to analyze longitudinal data and survival analysis to explore incident PSCI, controlling for demographic, clinical, and vascular indicators. Results: The prevalence of PSCI and mortality rate ranged from 34.6% to 53.7%, and 0 to 7.7% respectively, among 244 patients. Incidence of PSCI was 21.9%. While visual memory demonstrated a significant improvement (p<0.05), other cognitive domains showed a fluctuating yet stable pattern across visits (all ps>0.05). Besides age, baseline IQCODE (attention: -0.218 SD/y, executive function: -0.238 SD/y, visual memory: -0.266 SD/y), and MoCA improvement within 1 year (visuoconstruction: 0.007 SD/y, verbal memory: 0.012 SD/y) were associated with longitudinal cognitive changes. Baseline MoCA (OR=0.66, 95%CI=[0.59-0.74]), MoCA improvement within 3-6 months (OR=0.79, 95%CI=[0.71-0.89], and within 1 year (OR=0.86, 95%CI=[0.76-0.96]) were associated with long-term PSCI, while baseline MoCA (OR=0.76, 95%CI=[0.61-0.96]) was also associated with incident PSCI. Conclusion: While most domains remained stable across-time, visual memory demonstrated an overall improvement. Short-term cognitive improvement could be an early indicator of long-term cognitive trajectory to identify individuals who may be resilient to PSCI.

Pi-Shan Sung*, Kang-Po Lee*, Po-Yu Lin, Hui-Chen Su, Rwei-Ling Yu, Kuen-Jer Tsai, Sheng-Hsiang Lin, Chih-Hung Chen *These authors contributed equally to this work.
Factors Associated with Cognitive Outcomes After First-Ever Ischemic Stroke: The Impact of Small Vessel Disease Burden and Neurodegeneration
Abstract: Background: Differences exist regarding post-stroke cognitive outcomes. Objective: The aim of this study investigates the potential factors associated with post-stroke cognitive performance and trajectories. Methods: We performed a prospective cohort study using serial monitoring of cognitive function over a 1-year period after a first-ever ischemic stroke. Small vessel disease (SVD) burden and hippocampal atrophy (HA) were evaluated using the modified cerebral small vessel disease scores (mCSVD) and medial temporal atrophy score (MTA) scores. A generalized estimating equation (GEE) model and a group-based trajectory model (GBTM) was used to analyze the potential factors associated with post-stroke cognitive outcomes. Results: A total of 112 patients were enrolled. The GEE model showed that all patients, regardless of initial cognitive performance, had a tendency to show an increase in the Montreal Cognitive Assessment over time. The cognitive performance was better in male patients with higher education levels (p=0.046 and p<0.001, respectively), but tended to be worse in patients with higher SVD burden and HA. The GBTM model grouped patients into low, intermediate, and high performance (LP, IP, and HP) after stroke. A higher SVD burden, rather than HA and initial stroke severity and location, independently predicted a higher odds of poor post-stroke cognitive trajectory (being in the LP group) after stroke (adjusted odds ratio 2.74, 95% CI 1.09-6.86). Conclusion: In patients with first-ever mild stroke, cognitive improvement over time was evident. The detrimental impact of the SVD burden may outweigh the effect of HA or acute stroke insult on the post-stroke cognitive trajectory during the 1-year follow-up.

Samad Amini, Lifu Zhang, Boran Hao, Aman Gupta, Mengting Song, Cody Karjadi, Honghuang Lin, Vijaya B. Kolachalama, Rhoda Au, Ioannis Ch. Paschalidis
An Artificial Intelligence-Assisted Method for Dementia Detection Using Images from the Clock Drawing Test
Abstract: Background: Widespread dementia detection could increase clinical trial candidates and enable appropriate interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia-related disorders, it can be leveraged to develop a computer-aided screening tool. Objective: To evaluate if a machine learning model that uses images from the CDT can predict mild cognitive impairment or dementia. Methods: Images of an analog clock drawn by 3,263 cognitively intact and 160 impaired subjects were collected during in-person dementia evaluations by the Framingham Heart Study. We processed the CDT images, participant’s age, and education level using a deep learning algorithm to predict dementia status. Results: When only the CDT images were used, the deep learning model predicted dementia status with an area under the receiver operating characteristic curve (AUC) of 81.3% ± 4.3%. A composite logistic regression model using age, level of education, and the predictions from the CDT-only model, yielded an average AUC and average F1 score of 91.9% $plusmn; 1.1% and 94.6% ± 0.4%, respectively. Conclusion: Our modeling framework establishes a proof-of-principle that deep learning can be applied on images derived from the CDT to predict dementia status. When fully validated, this approach can offer a cost-effective and easily deployable mechanism for detecting cognitive impairment.

Jakub P. Hlávka, Andrew T. Kinoshita, Samantha Fang, Adriana Hunt
Clinical Outcome Measure Crosswalks in Alzheimer’s Disease: A Systematic Review
Abstract: Background: A key challenge in studies that model outcomes, disease progression, and cost-effectiveness of existing and emerging dementia treatments is the lack of conversion criteria to translate, or ‘crosswalk’, scores on multiple measurement scales. Clinical status in dementia is commonly characterized in the cognitive, functional, and behavioral domains. Objective: We conducted a systematic review of peer-reviewed dementia measure crosswalks in the three domains. Methods: We systematically reviewed published literature for crosswalks between scales used to measure cognitive, functional, or behavioral outcomes in Alzheimer’s and related dementias. The search was conducted in PubMed, and additional crosswalks were identified through snowballing and expert input from dementia modelers. Results: Of the reviewed articles, 2,334 were identified through a PubMed search, 842 articles were sourced from backward and forward citation snowballing, and 8 additional articles were recommended through expert input. 31 papers were eligible for inclusion, listing 74 unique crosswalks. Of those, 62 (83.8%) were between endpoints of the cognitive domain and 12 (16.2%) were either between endpoints of the functional domain or were hybrid in nature. Among crosswalks exclusively in the cognitive domain, a majority involved the Mini-Mental State Examination (MMSE) (37 crosswalks) or the Montreal Cognitive Assessment (MoCA) and its variants (25 crosswalks). MMSE was directly compared to MoCA or MoCA variants in 16 crosswalks. Conclusion: Existing crosswalks between measures of dementia focus largely on a limited selection of outcome measures, particularly MMSE and MoCA. Few crosswalks exist in the functional domain, and no crosswalks were identified for solely behavioral measures.

Pan Liu, Qian Yang, Ning Yu, Yan Cao, Xue Wang, Zhao Wang, Wen-ying Qiu, Chao Ma
Phenylalanine Metabolism is Dysregulated in Human Hippocampus with Alzheimer’s Disease Related Pathological Changes
Abstract: Background: Alzheimer’s disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated. Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination. Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared. Results: The results show that a pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples. Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation.

Mandy Melissa Jane Wittens, Diana Maria Sima, Ruben Houbrechts, Annemie Ribbens, Ellis Niemantsverdriet, Erik Fransen, Christine Bastin, Florence Benoit, Bruno Bergmans, Jean-Christophe Bier, Peter Paul De Deyn, Olivier Deryck, Bernard Hanseeuw, Adrian Ivanoiu, Jean-Claude Lemper, Eric Mormont, Gaëtane Picard, Ezequiel de la Rosa, Eric Salmon, Kurt Segers, Anne Sieben, Dirk Smeets, Hanne Struyfs, Evert Thiery, Jos Tournoy, Eric Triau, Anne-Marie Vanbinst, Jan Versijpt, Maria Bjerke, Sebastiaan Engelborghs
Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer’s Disease in a Clinical Setting: A REMEMBER Study
Abstract: Background: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer’s disease (AD) dementia (ADD) patients in selected research cohorts. Objective: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. Methods: The study population included HC (n=90), subjective cognitive decline (SCD, n=93), mild cognitive impairment (MCI, n=357), and ADD (n=280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n=820) images from a retrospective, multi-center study (REMEMBER), icobrain dm’s (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. Results: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC=0.914; Specificity 83.0%; Sensitivity 86.3%). Conclusion: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.

Andrea R. Zammit, Jingyun Yang, Aron S. Buchman, Sue E. Leurgans, Graciela Muniz-Terrera, Richard B. Lipton, Charles B. Hall, Patricia Boyle, David A. Bennett
Latent Cognitive Class at Enrollment Predicts Future Cognitive Trajectories of Decline in a Community Sample of Older Adults
Abstract: Background: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings. Objective: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change. Methods: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project. Results: A total of 1,662 individuals (mean age = 79.6 years, SD = 7.4, 75.4% female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n = 328, 19.7%), Average Cognition (n = 767, 46.1%), Mixed-Domains Impairment (n = 71, 4.3%), Memory-Specific Impairment (n = 274, 16.5%), and Frontal Impairment (n = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines. Conclusion: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up.

Wenying Du, Changchang Ding, Jiehui Jiang, Ying Han
Women Exhibit Lower Global Left Frontal Cortex Connectivity Among Cognitively Unimpaired Elderly Individuals: A Pilot Study from SILCODE
Abstract: Background: Mounting evidence suggests that sex differences exist in cognitive reserve (CR) for cognitively unimpaired (CU) elderly individuals. Global left frontal connectivity (gLFC connectivity) is a reliable neural substrate of CR. Objective: The purpose of this study was to explore sex differences in gLFC connectivity among CU elderly individuals. Methods: One hundred thirteen normal controls (NCs) (women=66) and 132 individuals with subjective cognitive decline (SCD) (women=92) were recruited from the Sino Longitudinal Study on Cognitive Decline (SILCODE) (data 1). Among them, 88 subjects underwent amyloid-β (Aβ) imaging, including 32 Aβ+ and 56 Aβ- subjects. Forty-six subjects underwent another rs-fMRI examination (data 2) to validate the repeatability of the calculation of gLFC connectivity, which was determined through seed-based functional connectivity between the LFC and voxels throughout the whole brain. Independent-sample t-tests were used to evaluate the sex differences in gLFC connectivity across different subgroups (NC versus SCD, Aβ+ versus Aβ-). Partial correlation analysis was used to calculate the correlations between gLFC connectivity and cognitive assessments. Results: Women exhibited lower gLFC connectivity in both the NC (p=0.001) and SCD (p=0.020) subgroups than men. Women also exhibited lower gLFC connectivity in both the Aβ- (p=0.006) and Aβ+ (p=0.025) groups. However, the significant difference disappeared in the Aβ+ group when considering the covariates of age, education, total intracranial volume, and APOE4-carrying status. In addition, gLFC connectivity values were negatively correlated with Geriatric Depression Scale scores in the SCD group (r=-0.176, p=0.047). Conclusion: Women showed lower gLFC connectivity among CU elderly individuals.

Wanyi Huang, Fan Zeng, Yebo Gu, Muzhou Jiang, Xinwen Zhang, Xu Yan, Tomoko Kadowaki, Shinsuke Mizutani, Haruhiko Kashiwazaki, Junjun Ni, Zhou Wu
Porphyromonas gingivalis Infection Induces Synaptic Failure via Increased IL-1β Production in Leptomeningeal Cells
Abstract: Background: Studies have reported that synaptic failure occurs before the Alzheimer’s disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. Objective: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. Methods: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). Results: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and Cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. Conclusion: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD.

Klodian Dhana, Bryan D. James, Puja Agarwal, Neelum T. Aggarwal, Laurel J. Cherian, Sue E. Leurgans, Lisa L. Barnes, David A. Bennett, Julie A. Schneider (Handling Associate Editor: Hannah Gardener)
MIND Diet, Common Brain Pathologies, and Cognition in Community-Dwelling Older Adults
Abstract: Background: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer’s disease (AD) dementia in older adults. Objective: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies. Methods: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOE ε4, late-life cognitive activities, and total energy intake. Results: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β=0.119, SE=0.040, p=0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE=0.037, p=0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β=0.121, SE=0.042, p=0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β=0.114, SE=0.050, p=0.023). Conclusion: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly.

Amber Nous, Mandy Melissa Jane Wittens, Yannick Vermeiren, Peter Paul De Deyn, Christine Van Broeckhoven, Guy Nagels, Ilse Smolders, Sebastiaan Engelborghs (Handling Associate Editor: Piotr Lewczuk)
Serum Daytime Melatonin Levels Reflect Cerebrospinal Fluid Melatonin Levels in Alzheimer’s Disease but Are Not Correlated with Cognitive Decline
Abstract: Background: Nocturnal cerebrospinal fluid (CSF) and blood melatonin levels are altered in Alzheimer’s disease (AD). However, literature remains inconclusive on daytime blood melatonin levels. A positive correlation between melatonin levels and Mini-Mental State Examination (MMSE) scores in AD subjects has been evidenced following cross-sectional analyses. Whereas a correlation between serum and spinal CSF melatonin has been shown in healthy volunteers, an equal investigation in AD patients still has to be undertaken. Objective: 1) To evaluate whether serum melatonin levels correlate with spinal CSF melatonin levels in AD. 2) To compare daytime CSF and serum melatonin levels between patients with AD dementia, mild cognitive impairment due to AD, and healthy controls, and to evaluate whether melatonin can affect cognitive decline in AD. Methods: Subjects with AD and healthy controls included in two existing cohorts, of whom a CSF and serum sample was available at the neurobiobank and had at least 6 months of neuropsychological follow-up, were included in the present study. Melatonin concentrations were measured with liquid chromatography-mass spectrometry. Results: Daytime serum melatonin levels correlated with spinal CSF melatonin levels in AD (r=0.751, p<0.001). No significant differences regarding daytime melatonin levels were found between patients and controls. No correlations were observed between daytime melatonin levels and MMSE score changes. Conclusion: Daytime serum melatonin accurately reflects CSF melatonin levels in AD, raising the possibility to assess melatonin alterations by solely performing blood sampling if also confirmed for night-time values. However, daytime melatonin levels are not associated with changes of cognitive impairment.

Laurens Ansem van de Mortel, Rajat Mani Thomas, Guido Alexander van Wingen for the Alzheimer’s Disease Neuroimaging Initiative
Grey Matter Loss at Different Stages of Cognitive Decline: A Role for the Thalamus in Developing Alzheimer's Disease
Abstract: Background: Alzheimer's disease (AD) is characterized by cognitive impairment and large loss of grey matter volume and is the most prevalent form of dementia worldwide. Mild cognitive impairment (MCI) is the stage that precedes the AD dementia stage, but individuals with MCI do not always convert to the AD dementia stage, and it remains unclear why. Objective: We aimed to assess grey matter loss across the brain at different stages of the clinical continuum of AD to gain a better understanding of disease progression. Methods: In this large-cohort study (N=1,386) using neuroimaging data from the Alzheimer’s Disease Neuroimaging Initiative, voxel-based morphometry analyses were performed between healthy controls, individuals with early and late and AD dementia stage. Results: Clear patterns of grey matter loss in mostly hippocampal and temporal regions were found across clinical stages, though not yet in early MCI. In contrast, thalamic volume loss seems one of the first signs of cognitive decline already during early MCI, whereas this volume loss does not further progress from late MCI to AD dementia stage. AD dementia stage converters already show grey matter loss in hippocampal and mid-temporal areas as well as the posterior thalamus (pulvinar) and angular gyrus at baseline. Conclusion: This study confirms the role of temporal brain regions in AD development and suggests additional involvement of the thalamus/pulvinar and angular gyrus that may be linked to visuospatial, attentional, and memory related problems in both early MCI and AD dementia stage conversion.

James E. Galvin, Iris Cohen, Keri K. Greenfield, Marcia Walker
The Frontal Behavioral Battery: A Measure of Frontal Lobe Symptoms in Brain Aging and Neurodegenerative Disease
Abstract: Background: Approximately 90% of persons living with dementia experience behavioral symptoms, including frontal lobe features involving motivation, planning, social behavior, language, personality, mood, swallowing, and gait. Objective: We conducted a two-stage study with a development sample (n=586) and validation sample (n=274) to evaluate a brief informant-rated measure of non-cognitive features of frontal lobe dysfunction: the Frontal Behavioral Battery (FBB). Methods: In the development sample, internal consistency, principal factor analysis, and correlations between the FBB and outcomes were evaluated. In the validation sample, we examined (a) FBB scores by diagnosis, (b) known-group validity by demographics, subjective complaints, and dementia staging, and (c) correlation between FBB and MRI volumes. Receiver operator characteristic curves assessed the ability of the FBB to discriminate individuals with frontal lobe features due to a neurodegenerative disease. Results: The FBB characterized 11 distinct frontal lobe features. Individuals with dementia with Lewy bodies and frontotemporal degeneration had the greatest number of frontal lobe features. Premorbid personality traits of extroversion, agreeableness, and openness were associated with fewer frontal lobe behavioral symptoms, while subjective cognitive complaints were associated with greater symptoms. The FBB provided very good discrimination between individuals with and without cognitive impairment (diagnostic odds ratio: 13.1) and between individuals with and without prominent frontal lobe symptoms (diagnostic odds ratio: 84.8). Conclusion: The FBB may serve as an effective and efficient method to assess the presence of non-cognitive symptoms associated with frontal lobe dysfunction, but in a brief fashion that could facilitate its use in clinical care and research.

Gorm Thorlacius-Ussing, Marie Bruun, Le Gjerum, Kristian S. Frederiksen, Hanneke F.M. Rhodius-Meester, Wiesje M. van der Flier, Gunhild Waldemar, Steen G. Hasselbalch (Handling Associate Editor: Flavio Nobili)
Comparing a Single Clinician Versus a Multidisciplinary Consensus Conference Approach for Dementia Diagnostics
Abstract: Background: Evidence-based recommendations on the optimal evaluation approach for dementia diagnostics are limited. This impedes a harmonized workup across clinics and nations. Objective: To evaluate the diagnostic performance of a multidisciplinary consensus conference compared to a single clinician approach. Methods: In this prospective study, we enrolled 457 patients with suspected cognitive decline, from two European memory clinics. A diagnostic evaluation was performed at baseline independently in two ways: 1) by a single clinician and 2) at a multidisciplinary consensus conference. A syndrome diagnosis and an etiological diagnosis was made. The confidence in the diagnosis was recorded using a visual analogue scale. An expert panel re-evaluation diagnosis served as reference for the baseline syndrome diagnosis and a 12-24-month follow-up diagnosis for the etiological diagnosis. Results: 439 patients completed the study. We observed 12.5% discrepancy (k=0.81) comparing the baseline syndrome diagnoses of the single clinician to the consensus conference, and 22.3% discrepancy (k=0.68) for the baseline etiological diagnosis. The accuracy of the baseline etiological diagnosis was significantly higher at the consensus conference and was driven mainly by increased accuracy in the MCI group. Confidence in the etiological diagnosis at baseline was significantly higher at the consensus conference (p < 0.005), especially for the frontotemporal dementia diagnosis. Conclusion: The multidisciplinary consensus conference performed better on diagnostic accuracy of disease etiology and increased clinicians’ confidence. This highlights the importance of a multidisciplinary diagnostic evaluation approach for dementia diagnostics, especially when evaluating patients in the MCI stage.

Ingrid Daae Rasmussen, Nya Mehnwolo Boayue, Matthias Mittner, Martin Bystad, Ole K. Grønli, Torgil Riise Vangberg, Gábor Csifcsák, Per M. Aslaksen (Handling Associate Editor: Jessica Peter)
High-Definition Transcranial Direct Current Stimulation Improves Delayed Memory in Alzheimer’s Disease Patients: A Pilot Study Using Computational Modeling to Optimize Electrode Position
Abstract: Background: The optimal stimulation parameters when using transcranial direct current stimulation (tDCS) to improve memory performance in patients with Alzheimer’s disease (AD) are lacking. In healthy individuals, inter-individual differences in brain anatomy significantly influence current distribution during tDCS, an effect that might be aggravated by variations in cortical atrophy in AD patients. Objective: To measure the effect of individualized HD-tDCS in AD patients. Methods: Nineteen AD patients were randomly assigned to receive active or sham high-definition tDCS (HD-tDCS). Computational modeling of the HD-tDCS-induced electric field in each patient’s brain was analyzed based on magnetic resonance imaging (MRI) scans. The chosen montage provided the highest net anodal electric field in the left dorsolateral prefrontal cortex (DLPFC). An accelerated HD-tDCS design was conducted (2 mA for 3 x 20 min) on two separate days. Pre- and post-intervention cognitive tests and T1 and T2-weighted MRI and diffusion tensor imaging data at baseline were analyzed. Results: Different montages were optimal for individual patients. The active HD-tDCS group improved significantly in delayed memory and MMSE performance compared to the sham group. Five participants in the active group had higher scores on delayed memory post HD-tDCS, four remained stable and one declined. The active HD-tDCS group had a significant positive correlation between fractional anisotropy in the anterior thalamic radiation and delayed memory score. Conclusion: HD-tDCS significantly improved delayed memory in AD. Our study can be regarded as a proof-of-concept attempt to increase tDCS efficacy. The present findings should be confirmed in larger samples.

Jordi A. Matias-Guiu, Vanesa Pytel, Laura Hernández-Lorenzo, Nikil Patel, Katie A. Peterson, Jorge Matías-Guiu, Peter Garrard, Fernando Cuetos
Spanish Version of the Mini-Linguistic State Examination for the Diagnosis of Primary Progressive Aphasia
Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main clinical variants: non-fluent, semantic, and logopenic. Clinical diagnosis and accurate classification are challenging and often time-consuming. The Mini-Linguistic State Examination (MLSE) has been recently developed as a short language test to specifically assess language in neurodegenerative disorders. Objective: Our aim was to adapt and validate the Spanish version of MLSE for PPA diagnosis. Methods: Cross-sectional study involving 70 patients with PPA and 42 healthy controls evaluated with the MLSE. Patients were independently diagnosed and classified according to comprehensive cognitive evaluation and advanced neuroimaging. Results: Internal consistency was 0.758. The influence of age and education was very low. The area under the curve for discriminating PPA patients and healthy controls was 0.99. Effect sizes were moderate-large for the discrimination between PPA and healthy controls. Motor speech, phonology, and semantic subscores discriminated between the three clinical variants. A random forest classification model obtained an F1-score of 81% for the three PPA variants. Conclusion: Our study provides a brief and useful language test for PPA diagnosis, with excellent properties for both clinical routine assessment and research purposes.

Haining He*, An Liu*, Wei Zhang*, Huanqing Yang, Minmin Zhang, Hua Xu, Yuanyuan Liu, Bo Hong, Feng Yan, Ling Yue, Jinghua Wang, Shifu Xiao, Zuoquan Xie, Tao Wang *These authors contributed equally to this work.
Novel Plasma miRNAs as Biomarkers and Therapeutic Targets of Alzheimer’s Disease at the Prodromal Stage
Abstract: Background: Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD) involving imbalanced beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). MicroRNAs (miRNAs) are associated with AD. Objective: This study aimed to investigated whether plasma miRNAs can predict prodromal AD or are associated with AD pathology. Methods: Participants in the discovery set (n=10), analysis set (n=30), and validation set (n=80) were screened from the China Longitudinal Aging Study. RNA was extracted from the participants’ plasma. Microarray sequencing provided miRNA profiles and differentially expressed miRNAs (DEmiRNAs) in the discovery set included patients with 18F-Flutemetamol positron emission tomography scan-confirmed aMCI. Potential biomarkers were screened in the analysis set. The predict capability of candidate miRNAs was assessed in the validation set. Candidate miRNAs modulation of BACE1 expression was explored in rat and human hippocampal neurons in vitro. Results: We verified 46 significant DEmiRNAs between the aMCI and NC groups (p < 0.05), among which 33 were downregulated. In the analysis set, miR-1185-2-3p, miR-1909-3p, miR-22-5p, and miR-134-3p levels decreased significantly in the aMCI group. These miRNAs and previously identified miR-107 were selected as potential biomarkers. A prediction model comprising these five miRNAs showed outstanding accuracy (81.25%) to discriminate aMCI at cut-off value of 0.174. Except for miR-134-3p, the other four miRNAs significantly suppressed Bace1 expression in rat hippocampal neurons in vitro. BACE1 modulation of miR-1185-2-3p, miR-1909-3p, and miR-134-3p was confirmed in human hippocampal neurons in vitro. Conclusion: A predictive model consisting of five BACE1-related plasma miRNAs could be a novel biomarker for aMCI.

Joost D. Wammes, Miharu Nakanishi, Jenny T. van der Steen, Janet L. MacNeil Vroomen
Japanese National Dementia Plan Is Associated with a Small Shift in Location of Death: An Interrupted Time Series Analysis
Abstract: Background: Japan has one of the highest percentages of persons with dementia and hospital deaths in the world. Hospitals are often not equipped to handle the care complexity required for persons with dementia at the end of life. The National Dementia Orange plan aimed to decrease hospital deaths by expanding time in the community. Objective: The aim of this study is to evaluate whether the National Dementia Orange Plan is associated with a decrease in hospitals deaths for persons with dementia. Methods: We used quarterly, cross-sectional, national death certificate data consisting of the total Japanese dementia population 65 years and older, spanning a period from 2009 to 2016. The primary outcome was quarterly adjusted relative risk rates (aRRR) of dying in hospital, nursing home, home, or elsewhere. An interrupted time series analysis was performed to study the slope change over time. Analyses were adjusted for sex and seasonality. Results: 149,638 died with dementia. With the implementation of the Orange Plan, death in nursing home (aRRR 1.08, [1.07-1.08], p < 0.001) and elsewhere (aRRR 1.05, [1.05-1.06], p < 0.001) increased over time compared to hospital death. No changes were found in death at home. Conclusion: This study provides evidence that the National Dementia Orange plan was associated with a small increase in death in nursing home and elsewhere. Hospital death remained the primary location of death. End-of-life strategies should be expanded in national dementia policies to increase aging in the community until death.

Hong-Yan Cai, Dan Yang, Jing Qiao, Jun-Ting Yang, Zhao-Jun Wang, Mei-Na Wu, Jin-Shun Qi, Christian Hölscher
A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion: DA4-JC is a promising drug for the treatment of AD.

Jie Zhou*, Luping Ma*, Lulei Zhao, Jiamin Sheng, Yuhua Xu, Jie Chen, Liangjun Yu, Quan Sun, Hangyang Zhou, Shaofeng Zhu1 Zefeng Lu, Bo Wei *These authors contributed equally to this work.
Association Between the Prognostic Nutritional Index and Cognitive Function Among Older Adults in the United States: A Population-Based Study
Abstract: Background: Nutritional status has been recognized as an important factor influencing cognitive function-related diseases, but few comprehensive nutrition indicators are available to assess the risk of cognitive decline. Objective: This study aimed to investigate the relationship between the prognostic nutritional index (PNI) and cognitive function in an elderly population, and the differences in nutrient intake between different levels of nutritional risk. Methods: Based on cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014, we included 2,564 older participants. The lower quartile of each of the four cognitive tests was considered to have cognitive function impairment (CFI). Binary and multivariate logistic regression models were used to estimate the relationship between the PNI and the odds ratio of CFI. Results: After adjustment for confounding variables, we found that the odds of CFI were significantly lower for participants with normal PNI levels than for those with low PNI levels. In a comparison of global cognitive impairment scores, participants with a normal PNI had lower ratios of poor cognitive performance than those with a low PNI. By comparing the nutrient intake at different PNI levels, we found a reduction in the intake of protein, dietary fiber, total saturated fatty acids, and multiple micronutrients in the low PNI group. Conclusion: Our study shows that the PNI can be a good predictor of the odds of CFI in the elderly population and that it is a convenient indicator of reduced intake of nutrients which may be important to brain health.

Yang Yu, Yang Gao, Bengt Winblad, Lars Tjernberg, Sophia Schedin Weiss
A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons
Abstract: Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

Benjamin Sweigart, Stacy L. Andersen, Anastasia Gurinovich, Stephanie Cosentino, Nicole Schupf, Thomas T. Perls, Paola Sebastiani (Handling Associate Editor: Robert Rissman)
APOE E2/E2 Is Associated with Slower Rate of Cognitive Decline with Age
Abstract: Background: The E4 allele of the APOE gene is known to be associated with cognitive impairment. However, a limited number of studies have examined the association between the E2 allele and longitudinal changes of cognitive function. Objective: To determine whether rates of cognitive change differ in carriers of the APOE E2 allele compared to other genotypes. Methods: We conducted a secondary analysis of data from two ongoing longitudinal cohort studies, the Long Life Family Study (LLFS) and New England Centenarian Study (NECS). We included participants who had APOE genotyping data, data from longitudinal administrations of the Telephone Interview for Cognitive Status (TICS), and age, sex, and education available. We assessed whether cognitive change as measured by rate of decline in TICS score differed among people with different APOE genotypes. We used a hierarchical mixed effect model with APOE genotypes, their interactions with age, and potential confounders. Results: After adjusting for sex and education, in carriers of the common E3/E3 genotype, TICS score decreased by 0.15 points per year of age. In those with the E2/E2 genotype, TICS score decreased by 0.05 points per year of age, a significantly slower rate of decline (p=0.017). We observed no protective effect of the E2/E3 genotype on cognitive decline. Conclusion: These results suggest a protective effect of the E2/E2 genotype on a measure of global cognitive function.

Shehroo B. Pudumjee, Emily S. Lundt, Sabrina M. Albertson, Mary M. Machulda, Walter K. Kremers, Clifford R. Jack, Jr., David S. Knopman, Ronald C. Petersen, Michelle M. Mielke, Nikki H. Stricker (Handling Associate Editor: Mark Bondi)
A Comparison of Cross-Sectional and Longitudinal Methods of Defining Objective Subtle Cognitive Decline in Preclinical Alzheimer’s Disease Based on Cogstate One Card Learning Accuracy Performance
Abstract: Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer’s disease continuum. Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (ΔOBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer’s disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance. Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50+ with amyloid and tau PET scans (n=311) comprised the biomarker-defined sample. A case-control sample of participants aged 65+ remaining cognitively unimpaired for at least 30 months included 64 who subsequently developed MCI (incident MCI cases) and 184 controls, risk-set matched by age, sex, education, and visit number. sOBJ was assessed by OCL z-scores. ΔOBJ was assessed using within subjects’ standard deviation and annualized change from linear regression or linear mixed effects (LME) models. Concordance measures Area Under the ROC Curve (AUC) or C-statistic and odds ratios (OR) from conditional logistic regression models were derived. sOBJ and ΔOBJ were modeled jointly to compare methods. Results: sOBJ and ΔOBJ-LME methods differentiated A+T+ from A-T- (AUC=0.64, 0.69) and controls from incident MCI (C-statistic=0.59, 0.69) better than chance; other ΔOBJ methods did not. ΔOBJ-LME improved prediction of future MCI over baseline sOBJ (p=0.003) but not over 30-month sOBJ (p=0.09). Conclusion: Longitudinal decline did not offer substantial benefit over cross-sectional assessment in detecting preclinical Alzheimer’s disease or incident MCI.

Alifiya Kapasi, Lei Yu, Christopher Stewart, Julie A. Schneider, David A. Bennett, Patricia A. Boyle
Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility
Abstract: Background: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer’s disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer’s disease (AD) pathology remains unclear. Objective: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. Methods: Data came from 198 deceased participants without clinical dementia (mean age at death=90 years; 69% women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. Results: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = -0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = -0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). Conclusion: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.

Xiao Liu*, Ayiguli Abudukeremu*, Yuan Jiang*, Zhengyu Cao, Maoxiong Wu, Runlu Sun, Zhiteng Cheng, Yangxin Chen, Yuling Zhang, Jingfeng Wang *These authors contributed equally to this work.
Fine or Gross Motor Index as a Simple Tool for Predicting Cognitive Impairment in Elderly People: Findings from The Irish Longitudinal Study on Ageing (TILDA)
Abstract: Background: Several kinds of motor dysfunction can predict future cognitive impairment in elderly individuals. However, the ability of the fine motor index (FINEA) and gross motor index (GROSSA) to predict the risk of cognitive impairment has not been assessed. Objective: We investigated the associations between FINEA/GROSSA and cognitive impairment. Methods: The data of 4,745 participants from The Irish Longitudinal Study on Ageing (TILDA) were analyzed. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). We first assessed the correlation between the FINEA GROSSA and MMSE in a cross-sectional study. Then, we further investigated the predictive role of the incidence of cognitive impairment in a prospective cohort study. Results: We found that both FINEA and GROSSA were negatively correlated with MMSE in both the unadjusted (FINEA: B=-1.00, 95% confidence intervals (CI): -1.17, -0.83, t=-11.53, p<0.001; GROSSA: B=-0.85, 95% CI: -0.94, -0.76, t=-18.29, p<0.001) and adjusted (FINEA: B=-0.63, 95% CI: -0.79, -0.47, t=-7.77, p<0.001; GROSSA: B=-0.57, 95% CI: -0.66, -0.48, t=-12.61, p<0.001) analyses in a cross-sectional study. In a prospective cohort study, both high FINEA and high GROSSA were associated with an increased incidence of cognitive function impairment (FINEA: adjusted odds ratios (OR)=2.35, 95% CI: 1.05, 5.23, p=0.036; GROSSA adjusted OR=3.00, 95% CI: 1.49, 6.03, p=0.002) after 2 years of follow-up. Conclusion: Higher FINEA and GROSSA scores were both associated with an increased incidence of cognitive impairment. FINEA or GROSSA might be a simple tool for identifying patients with cognitive impairment.

Wei Qin*, Wenwen Li*, Qi Wang, Min Gong, Tingting Li, Yuqing Shi, Yang Song, Ying Li, Fangyu Li, Jianping Jia *These authors contributed equally to this work.
Race-Related Association between APOE Genotype and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: The global race-dependent association of Alzheimer’s disease (AD) and apolipoprotein E (APOE) genotype is not well understood. Transethnic analysis of APOE could clarify the role of genetics in AD risk across populations. Objective: This study aims to determine how race and APOE genotype affect the risks for AD. Methods: We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library since 1993 to Aug 25, 2020. A total of 10,395 reports were identified, and 133 were eligible for analysis with data on 77,402 participants. Studies contained AD clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses. Odds ratios and 95% confidence intervals for developing AD were calculated for populations of different races and APOE genotypes. Results: The proportion of APOE genotypes and alleles differed between populations of different races. Results showed that APOE ε4 was a risk factor for AD, whereas APOE ε2 protected against it. The effects of APOE ε4 and ε2 on AD risk were distinct in various races, they were substantially attenuated among Black people. Sub-group analysis found a higher frequency of APOE ε4/ε4 and lower frequency of APOE ε3/ε3 among early-onset AD than late-onset AD in a combined group and different races. Conclusion: Our meta-analysis suggests that the association of APOE genotypes and AD differ between races. These results enhance our understanding of APOE-related risk for AD across race backgrounds and provide new insights into precision medicine for AD.

Angeliki Tsapanou, Panagiota Zoi, Faidra Kalligerou, Patra Blekou, Paraskevi Sakka
The Effect of Prolonged Lockdown Due to COVID-19 on Greek Demented Patients of Different Stages and on Their Caregivers
Abstract: Background: The impact of the new coronavirus disease (COVID-19) is deteriorating as time passes and the virus keeps spreading, with people with dementia and their caregivers being affected significantly. Objective: The aim of this study was to examine the effect of prolonged isolation because of the COVID-19 pandemic on people with dementia and their caregivers. Methods: Caregivers answered online questions regarding their own physical and psychological burden, and of the person they take care of. Participants were mostly members of online seminars of the Athens Alzheimer’s Association. Questions referred to their own burden, the overall decline of the persons they take care of, and changes in specific domains as well. Further, participants were asked about any changes between the two major lockdown periods. Analysis was performed including the total sample and then, by three different stages of dementia. Results: A total of 339 caregivers took part in the study. Results indicated significant decline, both in an overall aspect of the people with dementia, and in specific domains (mostly communication and mood). Regarding the caregivers, they reported having significantly increased physical and psychological burden, and also, noticing an overall change between the two lockdown periods in their own burden. Analysis by dementia-stage group indicated that significant decline occurred both in the middle-stage and the late-stage group. Conclusion: An urgency for further support of both the people with neurodegenerative disorders and their caregivers is needed. Collaboration among care workers, online programs, governmental support, and day-care centers should be planned to ensure continuity of care for those in need during the pandemic.

Chris J. Edgar, Eric Siemers, Paul Maruff, Ronald C. Petersen, Paul S. Aisen, Michael W. Weiner, Bruce Albala, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Montse Alegret)
Pilot Evaluation of the Unsupervised, At-Home Cogstate Brief Battery in ADNI-2
Abstract: Background: There is a need for feasible, scalable assessments to detect cognitive impairment and decline. The Cogstate Brief Battery (CBB) is validated for Alzheimer’s disease (AD) and in unsupervised and bring your own device contexts. The CBB has shown usability for self-completion in the home but has not been employed in this way in a multisite clinical trial in AD. Objective: The objective of the pilot was to evaluate feasibility of at-home, self-completion of the CBB in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) over 24 months. Methods: The CBB was included as a pilot for cognitively normal (CN) and mild cognitive impairment (MCI) participants in ADNI-2, invited to take the assessment in-clinic, then at at-home over a period of 24 months follow-up. Data were analyzed to explore acceptability/usability, concordance of in-clinic and at-home assessment, and validity. Results: Data were collected for 104 participants (46 CN, 51 MCI, and 7 AD) who consented to provide CBB data. Subsequent analyses were performed for the CN and MCI groups only. Test completion rates were 100% for both the first in-clinic supervised and first at-home unsupervised assessments, with few repeat performances required. However, availability follow-up data declined sharply over time. Good concordance was seen between in-clinic and at-home assessments, with non-significant and small effect size differences (Cohen’s d between -0.04 and 0.28) and generally moderate correlations (r = 0.42 to 0.73). Known groups validity was also supported (11/16 comparisons with Cohen’s d ≥ 0.3). Conclusion: These data demonstrate the feasibility of use for the CBB for unsupervised at-home, testing, including MCI groups. Optimal approaches to the application of assessments to support compliance over time remain to be determined.

Koh Tadokoro, Toru Yamashita, Shuhei Kimura, Emi Nomura, Yasuyuki Ohta, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Ryuta Morihara, Yuki Morizane, Koji Abe (Handling Associate Editor: Kenjiro Ono)
Retinal Amyloid Imaging for Screening Alzheimer’s Disease
Abstract: Background: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer’s disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. Objective: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. Methods: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. Results: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. Conclusion: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.