Volume 79, Number 2, 2021

Pages 467-476

Dorothee Horstkötter, Kay Deckers, Sebastian Köhler
Primary Prevention of Dementia: An Ethical Review
Abstract: Dementia poses important medical and societal challenges, and of all health risks people face in life, dementia is one of the most feared. Recent research indicates that up to about 40% of all cases of dementia might be preventable. A series of environmental, social, and medical risk-factors have been identified that should be targeted from midlife onwards when people are still cognitively healthy. At first glance, this seems not merely advisable, but even imperative. However, these new developments trigger a series of new ethical questions and concerns which have hardly been addressed to date. Pro-active ethical reflection, however, is crucial to ensure that the interests and well-being of those affected, ultimately all of us, are adequately respected. This is the goal of the current contribution. Against the background of a concrete case in primary dementia prevention, it provides a systematic overview of the current ethical literature and sketches an ethical research agenda. First, possible benefits of increased well-being must be balanced with the burdens of being engaged in particularly long-term interventions for which it is unclear whether they will ever pay out on a personal level. Second, while knowledge about one’s options to maintain brain health might empower people, it might also undermine autonomy, put high social pressure on people, medicalize healthy adults, and stigmatize those who still develop dementia. Third, while synergistic effects might occur, the ideals of dementia prevention might also conflict with other health and non-health related values people hold in life.

Pages 477-481
Short Communication

Tiziana Carandini*, Luca Sacchi*, Laura Ghezzi, Anna M. Pietroboni, Chiara Fenoglio, Andrea Arighi, Giorgio G. Fumagalli, Milena A. De Riz, Maria Serpente, Emanuela Rotondo, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Marco Bozzali) *These authors contributed equally to this work.
Detection of the SQSTM1 Mutation in a Patient with Early-Onset Hippocampal Amnestic Syndrome
Abstract: Genetics has a major role in early-onset dementia, but the correspondence to genotype-phenotype is largely tentative. We describe a 54-year-old with familial early-onset slowly-progressive episodic memory impairment with the P392L-variant in SQSTM1. The patient showed cortical atrophy and hypometabolism in the temporal lobes, but no amyloidosis biomarkers. As symptoms/neuroimaging were suggestive for Alzheimer’s disease—but biomarkers were not—and considering the family-history, genetic analysis was performed, revealing the P392L-variant in SQSTM1, which encodes for sequestosome-1/p62. Increasing evidence suggests a p62 involvement in neurodegeneration and SQSTM1 mutations have been found to cause amyotrophic lateral sclerosis/frontotemporal dementia. Our report suggests that the clinical spectrum of SQSTM1 variants is wider.

Pages 483-491
Yae Won Park, Dongmin Choi, Mina Park, Sung Jun Ahn, Sung Soo Ahn, Sang Hyun Suh, Seung-Koo Lee, Alzheimer’s Disease Neuroimaging Initiative
Predicting Amyloid Pathology in Mild Cognitive Impairment Using Radiomics Analysis of Magnetic Resonance Imaging
Abstract: Background: Noninvasive identification of amyloid-β (Aβ) is important for better clinical management of mild cognitive impairment (MCI) patients. Objective: To investigate whether radiomics features in the hippocampus in MCI improve the prediction of cerebrospinal fluid (CSF) Aβ42 status when integrated with clinical profiles. Methods: A total of 407 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative were allocated to training (n=324) and test (n=83) sets. Radiomics features (n=214) from the bilateral hippocampi were extracted from magnetic resonance imaging (MRI). A cut-off of < 192 pg/mL was applied to define CSF Aβ42 status. After feature selection, random forest with subsampling methods were utilized to develop three models with which to predict CSF Aβ42: 1) a radiomics model; 2) a clinical model based on clinical profiles; and 3) a combined model based on radiomics and clinical profiles. The prediction performances thereof were validated in the test set. A prediction model using hippocampus volume was also developed and validated. Results: The best-performing radiomics model showed an area under the curve (AUC) of 0.674 in the test set. The best-performing clinical model showed an AUC of 0.758 in the test set. The best-performing combined model showed an AUC of 0.823 in the test set. The hippocampal volume model showed a lower performance, with an AUC of 0.543 in the test set. Conclusion: Radiomics models from MRI can help predict CSF Aβ42 status in MCI patients and potentially triage the patients for invasive and costly Aβ tests.

Pages 493-509
Shumei Li*, Marcel Daamen*, Lukas Scheef, Florian C. Gaertner, Ralph Buchert, Martina Buchmann, Katharina Buerger, Cihan Catak, Laura Dobisch, Alexander Drzezga, Birgit Ertl-Wagner, Markus Essler, Klaus Fliessbach, John Dylan Haynes, Enise Irem Incesoy, Ingo Kilimann, Bernd J. Krause, Catharina Lange, Christoph Laske, Josef Priller, Alfredo Ramirez, Matthias Reimold, Axel Rominger, Nina Roy, Klaus Scheffler, Angelika Maurer, Anja Schneider, Annika Spottke, Eike Jakob Spruth, Stefan J. Teipel, Maike Tscheuschler, Michael Wagner, Steffen Wolfsgruber, Emrah Düzel, Frank Jessen, Oliver Peters, Henning Boecker, the DELCODE Study Group (Handling Associate Editor: Nasim Sheikh-Bahaei) *These authors contributed equally to this work.
Abnormal Regional and Global Connectivity Measures in Subjective Cognitive Decline Depending on Cerebral Amyloid Status
Abstract: Background: Amyloid-β accumulation was found to alter precuneus-based functional connectivity (FC) in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia, but its impact is less clear in subjective cognitive decline (SCD), which in combination with AD pathologic change is theorized to correspond to stage 2 of the Alzheimer’s continuum in the 2018 NIA-AA research framework. Objective: This study addresses how amyloid pathology relates to resting-state fMRI FC in SCD, especially focusing on the precuneus. Methods: From the DELCODE cohort, two groups of 24 age- and gender-matched amyloid-positive (SCDAβ+) and amyloid-negative SCD (SCDAβ-) patients were selected according to visual [18F]-Florbetaben (FBB) PET readings, and studied with resting-state fMRI. Local (regional homogeneity [ReHo], fractional amplitude of low-frequency fluctuations [fALFF]) and global (degree centrality [DC], precuneus seed-based FC) measures were compared between groups. Follow-up correlation analyses probed relationships of group differences with global and precuneal amyloid load, as measured by FBB standard uptake value ratios (SUVRFBB). Results: ReHo was significantly higher (voxel-wise p<0.01, cluster-level p<0.05) in the bilateral precuneus for SCDAβ+ patients, whereas fALFF was not altered between groups. Relatively higher precuneus-based FC with occipital areas (but no altered DC) was observed in SCDAβ+ patients. In this latter cluster, precuneus-occipital FC correlated positively with global (SCDAβ+) and precuneus SUVRFBB (both groups). Conclusion: While partial confounding influences due to a higher APOE ε4 carrier ratio among SCDAβ+ patients cannot be excluded, exploratory results indicate functional alterations in the precuneus hub region that were related to amyloid-β load, highlighting incipient pathology in stage 2 of the AD continuum.

Pages 511-530
Miles Berger, Mary Cooter, Alexander S. Roesler, Stacey Chung, John Park, Jennifer L. Modliszewski, Keith W. VanDusen, J. Will Thompson, Arthur Moseley, Michael J. Devinney, Shayan Smani, Ashley Hall, Victor Cai, Jeffrey N. Browndyke, Michael W. Lutz, David L. Corcoran, Alzheimer’s Disease Neuroimaging Initiative
APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid
Abstract: Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q < 0.05 for each), and with significant increases in ALDOA, CH3L1 (YKL-40), and FABPH peptide levels (q < 0.05 for each) except when controlling for AD clinical status or neurodegeneration biomarkers (i.e., CSF tau or p-tau). In all models except the one controlling for CSF Aβ levels, though not statistically significant, there was a consistent inverse direction of association between APOE4 copy number and the levels of all 24 peptides from all 8 different complement proteins measured. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million. Conclusion: Increasing APOE4 copy number was associated with decreased CSF CRP levels across all models, and increased CSF ALDOA, CH3L1, and FABH levels when controlling for CSF Aβ levels. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.

Pages 531-541
Yang Jiang, Juan Li, Frederick A. Schmitt, Gregory A. Jicha, Nancy B. Munro, Xiaopeng Zhao, Charles D. Smith, Richard J. Kryscio, Erin L. Abner
Memory-Related Frontal Brainwaves Predict Transition to Mild Cognitive Impairment in Healthy Older Individuals Five Years Before Diagnosis
Abstract: Background: Early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer’s disease. We have developed individualized measures in electrophysiological brain signals during working memory that distinguish patients with aMCI from age-matched cognitively intact older individuals. Objective: Here we test longitudinally the prognosis of the baseline neuromarkers for aMCI risk. We hypothesized that the older individuals diagnosed with incident aMCI already have aMCI-like brain signatures years before diagnosis. Methods: Electroencephalogram (EEG) and memory performance were recorded during a working memory task at baseline. The individualized baseline neuromarkers, annual cognitive status, and longitudinal changes in memory recall scores up to 10 years were analyzed. Results: Seven of the 19 cognitively normal older adults were diagnosed with incident aMCI for a median 5.2 years later. The seven converters’ frontal brainwaves were statistically identical to those patients with diagnosed aMCI (n=14) at baseline. Importantly, the converters’ baseline memory-related brainwaves (reduced mean frontal responses to memory targets) were significantly different from those who remained normal. Furthermore, differentiation pattern of left frontal memory-related responses (targets versus nontargets) was associated with an increased risk hazard of aMCI (HR = 1.47, 95% CI 1.03, 2.08). Conclusion: The memory-related neuromarkers detect MCI-like brain signatures about five years before diagnosis. The individualized frontal neuromarkers index increased MCI risk at baseline. These noninvasive neuromarkers during our Bluegrass memory task have great potential to be used repeatedly for individualized prognosis of MCI risk and progression before clinical diagnosis.

Pages 543-557
Charles F. Murchison, Richard E. Kennedy, Jonathan E. McConathy, Erik D. Roberson
Racial Differences in Alzheimer’s Disease Specialist Encounters Are Associated with Usage of Molecular Imaging and Dementia Medications: An Enterprise-Wide Analysis Using i2b2
Abstract: Background: African Americans are at increased risk for Alzheimer’s disease (AD) but barriers to optimal clinical care are unclear. Objective: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center. Methods: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts. Results: Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered. Conclusion: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand.

Pages 559-572
Jessica Mozersky, Sarah Hartz, Erin Linnenbringer, Lillie Levin, Marissa Streitz, Kristin Stock, Krista Moulder, John C. Morris
Communicating 5-Year Risk of Alzheimer’s Disease Dementia: Development and Evaluation of Materials that Incorporate Multiple Genetic and Biomarker Research Results
Abstract: Background: Cognitively normal (CN) older adults participating in Alzheimer’s disease (AD) research increasingly ask for their research results—including genetic and neuroimaging findings—to understand their risk of developing AD dementia. AD research results are typically not returned for multiple reasons, including possible psychosocial harms of knowing one is at risk of a highly feared and untreatable disease. Objective: We developed materials that convey information about 5-year absolute risk of developing AD dementia based on research results. Methods: 20 CN older adults who received a research brain MRI result were interviewed regarding their wishes for research results to inform material development (Pilot 1). Following material development, 17 CN older adults evaluated the materials for clarity and acceptability (Pilot 2). All participants were community-dwelling older adults participating in longitudinal studies of aging at a single site. Results: Participants want information on their risk of developing AD dementia to better understand their own health, satisfy curiosity, inform family, and future planning. Some articulated concerns, but the majority wanted to know their risk despite the limitations of information. Participants found the educational materials and results report clear and acceptable, and the majority would want to know their research results after reviewing them. Conclusion: These materials will be used in a clinical study examining the psychosocial and cognitive effects of offering research results to a cohort of CN older adults. Future AD research may incorporate the return of complex risk information to CN older adults, and materials are needed to communicate this information.

Pages 573-584
Yusuke Seino, Takumi Nakamura, Tomoo Harada, Naoko Nakahata, Takeshi Kawarabayashi, Tetsuya Ueda, Masamitsu Takatama, Mikio Shoji
Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry
Abstract: Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38, 2199±725 pmol/L in Aβ1-40, 153.7±79.7 pmol/L in Aβ1-42, and 9.78±4.58 pmol/L in Aβ1-43. The ratio of the amounts of Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42, Aβ1-38/1-43, and Aβ1-40/Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.

Pages 585-595
Qiang Wang*, Ben Chen*, Xiaomei Zhong*, Huarong Zhou, Min Zhang, Naikeng Mai, Zhangying Wu, Xingxiao Huang, Antje Haehner, Xinru Chen, Lavinia Alberi Auber, Qi Peng, Thomas Hummel, Yuping Ning *These authors contributed equally to this work.
Olfactory Dysfunction Is Already Present with Subjective Cognitive Decline and Deepens with Disease Severity in the Alzheimer’s Disease Spectrum
Abstract: Background: Odor identification dysfunction occurs early in Alzheimer’s disease (AD) and is considered a preclinical symptom along with subjective cognitive decline (SCD). Nevertheless, whether subjects with SCD are co-symptomatic with odor identification dysfunction remains unclear. Objective: To compare the degree of odor identification dysfunction and assess the relation between odor identification and cognitive performance in the AD spectrum (including SCD, mild cognitive impairment (MCI), and AD). Methods: Patients (84 SCD, 129 MCI, 52 AD) and 35 controls underwent the Sniffin’ Sticks Screen 16 test and comprehensive neuropsychological examination. Results: Odor identification scores were progressively lower moving from normal older adult to SCD, MCI, and AD. Additionally, the proportion of odor identification dysfunction were increasingly higher in the AD spectrum (p for trend <0.001), but no significant difference was found in the proportion of subjective olfactory dysfunction. No significant correlation was found between odor identification and cognition in the normal older adults and SCD subjects, but odor identification correlated with global cognition in the MCI (r=0.199, p=0.033) and in the AD (r=0.300, p=0.036) patients. Multiple linear regression showed that odor identification dysfunction was most strongly associated with memory among different cognitive subdomains and was most strongly associated with immediate verbal recall among different memory subdomains. Conclusion: Odor identification dysfunction is already present with SCD and deepens with disease severity in the AD spectrum, and it may contribute to predicting cognitive decline and identifying SCD subjects who are at risk of developing AD.

Pages 597-605
Pablo Bascuñana, Mirjam Brackhan, Jens Pahnke
Machine Learning-Supported Analyses Improve Quantitative Histological Assessments of Amyloid-β Deposits and Activated Microglia
Abstract: Background: Detailed pathology analysis and morphological quantification is tedious, prone to errors. Automatic image analysis can help to increase objectivity and reduce time. Here, we present the evaluation of the DeePathology STUDIOTM for automatic analysis of histological whole-slide images using machine learning/artificial intelligence. Objective: To evaluate and validate the use of DeePathology STUDIO for the analysis of histological slides at high resolution. Methods: We compared the DeePathology STUDIO and our current standard method using macros in AxioVision for the analysis of amyloid-β (Aβ) plaques and microglia in APP-transgenic mice at different ages. We analyzed density variables and total time invested with each approach. In addition, we correlated Aβ concentration in brain tissue measured by ELISA with the results of Aβ staining analysis. Results: DeePathology STUDIO showed a significant decrease of the time for establishing new analyses and the total analysis time by up to 90%. On the other hand, both approaches showed similar quantitative results in plaque and activated microglia density in the different experimental groups. DeePathology STUDIO showed higher sensitivity and accuracy for small-sized plaques. In addition, DeePathology STUDIO allowed the classification of plaques in diffuse- and dense-packed, which was not possible with our traditional analysis. Conclusion: DeePathology STUDIO substantially reduced the effort needed for a new analysis showing comparable quantitative results to the traditional approach. In addition, it allowed including different objects (categories) or cell types in a single analysis, which is not possible with conventional methods.

Pages 607-613
Xiuzhe Wang, Zhijuan Miao, Xiaofeng Xu, Marianne Schutlzberg, Yuwu Zhao
Reduced Levels of Plasma Lipoxin A4 Are Associated with Post-Stroke Cognitive Impairment
Abstract: Background: Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer’s disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI). Objective: In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke. Methods: Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay. Results: We found that levels of the SPM lipoxin A4 (LXA4) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, resolvin E1, and maresin 1. Conclusion: We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function.

Pages 615-625
Jennifer Ailshire, Katrina M. Walsemann
Education Differences in the Adverse Impact of PM2.5 on Incident Cognitive Impairment Among U.S. Older Adults
Abstract: Background: Air pollution is linked to worse cognitive function in older adults, but whether differences in this relationship exist by education, a key risk factor for cognitive decline, remains unknown. Objective: To determine if the association between fine particulate matter air pollution (PM2.5) and incident cognitive impairment varies by level of education in two cohorts assessed a decade apart. Methods: We used data on adults ages 60 and older from the nationally representative Health and Retirement Study (HRS) linked with tract-level annual average PM2.5. We used mixed-effects logistic regression models to examine education differences in the association between PM2.5 and incident cognitive impairment in two cohorts: 2004 (n=9,970) and 2014 (n=9,185). Cognitive impairment was determined with tests of memory and processing speed for self-respondents and proxy and interviewer assessments of cognitive functioning in non-self-respondents. Results: PM2.5 was unrelated to incident cognitive impairment among those with 13 or more years of education, but the probability of impairment increased with greater concentrations of PM2.5 among those with 8 or fewer years of education. The interaction between education and PM2.5 was only found in 2004, possibly because PM2.5 concentrations were much lower in 2014. Conclusion: Education is a key determinant of cognitive decline and impairment, and in higher pollution contexts may serve as a protective factor against the harms of air pollution on the aging brain. Additionally, because air pollution is ubiquitous, and particularly harmful to vulnerable populations, even small improvements in air quality may have large impacts on population health.

Pages 627-637
Kazuko Hasegawa, Kenji Kochi, Hidenori Maruyama, Osamu Konishi, Shunji Toya, Toshinari Odawara
Efficacy and Safety of Zonisamide in Dementia with Lewy Bodies Patients with Parkinsonism: A Post Hoc Analysis of Two Randomized, Double-Blind, Placebo-Controlled Trials
Abstract: Background: Although previous phase II and III clinical trials conducted in Japan showed that zonisamide improved parkinsonism in patients with dementia with Lewy bodies (DLB), some differences in efficacy outcomes were observed between the trials. Objective: We aimed to further examine the efficacy and safety of zonisamide in DLB patients with parkinsonism in a post hoc analysis of pooled data from the previous phase II and III trials. Methods: Both trials featured a 4-week run-in period followed by a 12-week treatment period with a double-blind, placebo-controlled, parallel-group, randomized, multicenter trial design. In our pooled analysis, the primary outcome was the change in Unified Parkinson’s Disease Rating Scale (UPDRS) part III total score. Other outcomes included the changes in Mini-Mental State Examination (MMSE) and Neuropsychiatric Inventory-10 (NPI-10) scores, and the incidence of adverse events. Results: Zonisamide significantly decreased the UPDRS part III total and individual motor symptom scores but did not affect the MMSE or NPI-10 scores at week 12. There was no difference in the incidence of adverse events between the zonisamide and placebo groups except for decreased appetite, which had an increased frequency in the zonisamide 50-mg group compared with placebo. Conclusion: Our findings indicate that zonisamide improved parkinsonism with DLB without deterioration of cognitive function or worsening behavioral and psychological symptoms of dementia.

Pages 639-652
Daisuke Ibi, Kazuki Hirashima, Yuya Kojima, Kahori Sumiya, Sari Kondo, Mirai Yamamoto, Toshihiro Ando, Masayuki Hiramatsu (Handling Associate Editor: Kazuyuki Takata)
Preventive Effects of Continuous Betaine Intake on Cognitive Impairment and Aberrant Gene Expression in Hippocampus of 3xTg Mouse Model of Alzheimer’s Disease
Abstract: Background: The deposition of amyloid-β (Aβ) and hyperphosphorylation of tau are well-known as the pathophysiological features of Alzheimer’s disease (AD), leading to oxidative stress and synaptic deficits followed by cognitive symptoms. We already demonstrated that betaine (glycine betaine) prevented cognitive impairment and hippocampal oxidative stress in mice intracerebroventricularly injected with an active fragment of Aβ, whereas the effect of betaine in chronic models of AD remains unknown. Objective: Our objective was to investigate the effects of chronic betaine intake on cognitive impairment and aberrant expression of genes involved in synapse and antioxidant activity in the hippocampus of a genetic AD model. Methods: We performed cognitive tests and RT-PCR in the hippocampus in 3xTg mice, a genetic AD model. Results: Cognitive impairment in the Y-maze and novel object recognition tests became evident in 3xTg mice at 9 months old, and not earlier, indicating that cognitive impairment in 3xTg mice developed age-dependently. To examine the preventive effect of betaine on such cognitive impairment, 3xTg mice were fed betaine-containing water for 3 months from 6 to 9 months old, and subsequently subjected to behavioral tests, in which betaine intake prevented the development of cognitive impairment in 3xTg mice. Additionally, the expression levels of genes involved in synapse and antioxidant activity were downregulated in hippocampus of 3xTg mice at 9 months old compared with age-matched wild-type mice, which were suppressed by betaine intake. Conclusion: Betaine may be applicable as an agent preventing the progression of AD by improving the synaptic structure/function and/or antioxidant activity.

Pages 653-661
Guanqun Chen, Mingyan Zhao, Kun Yang, Hua Lin, Chunlei Han, Xiaoni Wang, Ying Han (Handling Associate Editor: Ling-Qiang Zhu)
Education Exerts Different Effects on Cognition in Individuals with Subjective Cognitive Decline and Cognitive Impairment: A Population-Based Study
Abstract: Background: Education plays a potential important effect on the prevalence and incidence of dementia. However, most of the evidence based on convenience sampling. Objective: To explore effects of education on cognition in individuals with subjective cognitive decline (SCD) and cognitive impairment (CI) from a population-based study. Methods: We examined the effect of education on cognition among individuals with SCD (n=451) and CI (n=280) from a population-based study. A series of neuropsychological tests of memory, executive, language, and general cognitive function were used to assess the participants. Results: Multiple regression analyses revealed that education has a positive effect on cognition in both SCD and CI group in the population‐based research. Further stratification study showed that the beneficial effect of education remains in the SCD group regardless of the education level, especially in the SCD participants with a low education level. However, that effect of education exists in the CI group with a low education level and disappears in the high education level. Conclusion: These results from a population-based sample suggest that high educational attainment may delay cognitive decline in the individuals with SCD regardless of high or low educational level, and high education only predicts cognition in those in the low educational level in CI group.

Pages 663-670
Stefan J. Teipel, Anna Gesine Marie Temp, Fedor Levin, Martin Dyrba, Michel J. Grothe, for the Alzheimer’s Disease Neuroimaging Initiative*
Association of TDP-43 Pathology with Global and Regional 18F-Florbetapir PET Signal in the Alzheimer’s Disease Spectrum
Abstract: Background: TAR DNA-binding protein 43 (TDP-43) has been recognized as a frequent co-pathology of Alzheimer’s disease (AD). The effect of the presence of TDP-43 pathology on in vivo measures of AD-related amyloid pathology using amyloid sensitive PET is still unresolved. Objective: To study the association of TDP-43 pathology with antemortem amyloid PET signal. Methods: We studied 30 cases from the ADNI autopsy sample with available ratings of presence of TDP-43 and antemortem amyloid sensitive 18F-FlorbetapirPET. We used Bayesian regression to determine the effect of TDP-43 on global and regional amyloid PET signal. In a post-hoc analysis, we assessed the association of TDP-43 pathology with antemortem memory performance. Results: We found substantial to strong evidence for a negative effect of TDP-43 (Bayes factor against the null model (BF10) = 9.0) and hippocampal sclerosis (BF10 = 6.4) on partial volume corrected hippocampal 18F-Florbetapir uptake. This effect was only partly mediated by the negative effect of TDP-43 on hippocampal volume. In contrast, Bayesian regression supported that there is no effect of TDP-43 on global cortical PET-signal (BF10 = 0.65). We found an anecdotal level of evidence for a negative effect of TDP-43 pathology on antemortem memory performance after accounting for global amyloid PET signal (BF10 = 1.6). Conclusion: Presence of TDP-43 pathology does not confound the global amyloid PET-signal but has a selective effect on hippocampal PET-signal that appears only partially dependent on TDP-43 mediated atrophy.

Pages 671-681
Melissa E. Petersen, Michael S. Rafii, Fan Zhang, James Hall, David Julovich, Beau M. Ances, Nicole Schupf, Sharon J. Krinsky-McHale, Mark Mapstone, Wayne Silverman, Ira Lott, William Klunk, Elizabeth Head, Brad Christian, Tatiana Foroud, Florence Lai, H. Diana Rosas, Shahid Zaman, Mei-Cheng Wang, Benjamin Tycko, Joseph Lee, Benjamin Handen, Sigan Hartley, Juan Fortea, Sid O’Bryant; for the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS)
Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome
Abstract: Background: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods: Plasma samples were analyzed from n=305 (n=225 cognitively stable (CS); n=44 MCI-DS; n=36 DS-AD) participants enrolled in the Alzheimer’s Biomarker Consortium – Down Syndrome. Results: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Pages 683-691
Matteo Tagliapietra, Emma Frasson, Davide Cardellini, Sara Mariotto, Sergio Ferrari, Gianluigi Zanusso, Mauro Plebani, Salvatore Monaco
Hypothalamic-Bulbar MRI Hyperintensity in Anti-IgLON5 Disease with Serum-Restricted Antibodies: A Case Report and Systematic Review of Literature
Abstract: Background: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing. Objective: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum. Methods: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature. Results: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients. Conclusion: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.

Pages 693-708
Ryan J. Keenan, Sara Oberrauch, Romke Bron, Cameron J. Nowell, Leesa M. Challis, Daniel Hoyer, Laura H. Jacobson (Handling Associate Editor: Claudio Liguori)
Decreased Orexin Receptor 1 mRNA Expression in the Locus Coeruleus in Both Tau Transgenic rTg4510 and Tau Knockout Mice and Accompanying Ascending Arousal System Tau Invasion in rTg4510
Abstract: Background: Sleep/wake disturbances (e.g., insomnia and sleep fragmentation) are common in neurodegenerative disorders, especially Alzheimer’s disease (AD) and frontotemporal dementia (FTD). These symptoms are somewhat reminiscent of narcolepsy with cataplexy, caused by the loss of orexin-producing neurons. A bidirectional relationship between sleep disturbance and disease pathology suggests a detrimental cycle that accelerates disease progression and cognitive decline. The accumulation of brain tau fibrils is a core pathology of AD and FTD-tau and clinical evidence supports that tau may impair the orexin system in AD/FTD. This hypothesis was investigated using tau mutant mice. Objective: To characterize orexin receptor mRNA expression in sleep/wake regulatory brain centers and quantify noradrenergic locus coeruleus (LC) and orexinergic lateral hypothalamus (LH) neurons, in tau transgenic rTg4510 and tau-/- mice. Methods: We used in situ hybridization and immunohistochemistry (IHC) in rTg4510 and tau-/- mice. Results: rTg4510 and tau-/- mice exhibited a similar decrease in orexin receptor 1 (OX1R) mRNA expression in the LC compared with wildtype controls. IHC data indicated this was not due to decreased numbers of LC tyrosine hydroxylase-positive (TH) or orexin neurons and demonstrated that tau invades TH LC and orexinergic LH neurons in rTg4510 mice. In contrast, orexin receptor 2 (OX2R) mRNA levels were unaffected in either model. Conclusion: The LC is strongly implicated in the regulation of sleep/wakefulness and expresses high levels of OX1R. These findings raise interesting questions regarding the effects of altered tau on the orexin system, specifically LC OX1Rs, and emphasize a potential mechanism which may help explain sleep/wake disturbances in AD and FTD.

Pages 709-727
Hortense Fanet, Marine Tournissac, Manon Leclerc, Vicky Caron, Cyntia Tremblay, Sylvie Vancassel*, Frédéric Calon* (Handling Associate Editor: Othman Ghribi) *These authors share senior authorship.
Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer’s Disease, Without Altering Amyloid-β and Tau Pathologies
Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment. Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat – CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies. Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic symptoms accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.

Pages 729-741
Karolina Minta, Gunnar Brinkmalm, Erik Portelius, Per Johansson, Johan Svensson, Petronella Kettunen, Anders Wallin, Henrik Zetterberg, Kaj Blennow, Ulf Andreasson (Handling Associate Editor: Jagan Pillai)
Brevican and Neurocan Peptides as Potential Cerebrospinal Fluid Biomarkers for Differentiation Between Vascular Dementia and Alzheimer’s Disease
Abstract: Background: Brevican and neurocan are central nervous system-specific extracellular matrix proteoglycans. They are degraded by extracellular enzymes, such as metalloproteinases. However, their degradation profile is largely unexplored in cerebrospinal fluid (CSF). Objective: The study aim was to quantify proteolytic peptides derived from brevican and neurocan in human CSF of patients with Alzheimer’s disease (AD) and vascular dementia (VaD) compared with controls. Methods: The first cohort consisted of 75 individuals including 25 patients with AD, 7 with mild cognitive impairment (MCI) diagnosed with AD upon follow-up, 10 patients with VaD or MCI diagnosed with VaD upon follow-up, and 33 healthy controls and cognitively stable MCI patients. In the second cohort, 31 individuals were included (5 AD patients, 14 VaD patients and 12 healthy controls). Twenty proteolytic peptides derived from brevican (n=9) and neurocan (n=11) were quantified using high-resolution parallel reaction monitoring mass spectrometry. Results: In the first cohort, the majority of CSF concentrations of brevican and neurocan peptides were significantly decreased in VaD as compared with AD patients (AUC=0.83-0.93, p≤0.05) and as compared with the control group (AUC=0.79-0.87, p≤0.05). In the second cohort, CSF concentrations of two brevican peptides (B87, B156) were significantly decreased in VaD compared with AD (AUC=0.86-0.91, p≤0.05) and to controls (AUC=0.80-0.82, p≤0.05), while other brevican and neurocan peptides showed a clear trend to be decreased in VaD compared with AD (AUC=0.64-80, p>0.05). No peptides differed between AD and controls. Conclusion: Brevican and neurocan peptides are potential diagnostic biomarkers for VaD, with ability to separate VaD from AD.

Pages 743-762
Andrea M. McGrattan, Yueping Zhu, Connor D. Richardson, Devi Mohan, Yee Chang Soh, Ayesha Sajjad, Carla van Aller, Shulin Chen, Stella-Maria Paddick, Matthew Prina, Mario Siervo, Louise A. Robinson, Blossom C.M. Stephan
Prevalence and Risk of Mild Cognitive Impairment in Low and Middle-Income Countries: A Systematic Review
Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state associated with increased risk of dementia. Little research on MCI exists from low-and middle-income countries (LMICs), despite high prevalence of dementia in these settings. Objective: This systematic review aimed to review epidemiological reports to determine the prevalence of MCI and its associated risk factors in LMICs. Methods: Medline, Embase, and PsycINFO were searched from inception until November 2019. Eligible articles reported on MCI in population or community-based studies from LMICs. No restrictions on the definition of MCI used as long as it was clearly defined. Results: 4,621 articles were screened, and 78 retained. In total, n=23 different LMICs were represented; mostly from China (n=55 studies). Few studies from countries defined as lower-middle income (n=14), low income (n=4), or from population representative samples (n=4). There was large heterogeneity in how MCI was diagnosed; with Petersen criteria the most commonly applied (n=26). Prevalence of aMCI (Petersen criteria) ranged from 0.6% to 22.3%. Similar variability existed across studies using the International Working Group Criteria for aMCI (range 4.5% to 18.3%) and all-MCI (range 6.1% to 30.4%). Risk of MCI was associated with demographic (e.g., age), health (e.g., cardio-metabolic disease), and lifestyle (e.g., social isolation, smoking, diet and physical activity) factors. Conclusion: Outside of China, few MCI studies have been conducted in LMIC settings. There is an urgent need for population representative epidemiological studies to determine MCI prevalence in LMICs. MCI diagnostic methodology also needs to be standardized. This will allow for cross-study comparison and future resource planning.

Pages 763-771
Maria Basta, Ioannis Zaganas, Panagiotis Simos, Eirini Koutentaki, Christina Dimovasili, Lambros Mathioudakis, Mara Bourbouli, Symeon Panagiotakis, Stefania Kapetanaki, Alexandros Vgontzas
Apolipoprotein E ε4 (APOE ε4) Allele Is Associated with Long Sleep Duration Among Elderly with Cognitive Impairment
Abstract: Background: Apolipoprotein E gene (APOE) ε4 allele increases the risk for Alzheimer’s disease (AD). Furthermore, among patients with cognitive impairment, longer sleep duration is associated with worse cognitive performance. To date, literature examining the associations between APOE ε4 allele and objective sleep duration is limited. Objective: Our aim was to assess the association between APOE ε4 and objective sleep duration, among patients with mild cognitive impairment (MCI) and AD. A sub-sample of 89 patients with AD (n=49) and MCI (n=40) were recruited from a large, population-based cohort of 3,140 elders (>60 years) residing on Crete, Greece. Methods: All participants underwent medical history/physical examination, extensive neuropsychiatric and neuropsychological evaluation, 3-day 24-h actigraphy and APOE ε4 allele genotyping. Comparisons of sleep duration variables between APOE ε4 allele carriers and non-carriers were assessed using ANCOVA, controlling for confounders. Results: The sample included 18 APOE ε4 carriers and 71 non-carriers, aged 78.6±6.6 and 78.2±6.5 years, respectively. Comparisons between the APOE ε4 carriers and non-carriers revealed no significant differences in terms of demographic and clinical variables. In terms of objective sleep duration across the two groups, APOE ε4 carriers compared to non-carriers had significantly longer nighttime Total Sleep Time (nTST) (7.7±1.4 versus 7.2±1.3 h, respectively, p=0.011), as well as 24-h TST (8.5±1.6 versus 7.8±1.5 h, respectively, p=0.012). Conclusion: Among patients with MCI and AD, APOE ε4 carriers have longer objective nighttime and 24-h sleep duration compared to non-carriers. These findings further support that objective long sleep duration is a genetically-driven pre-clinical marker associated with worse prognosis in elderly with cognitive impairment.

Pages 773-792
Julian Hirt, Nicola Ballhausen, Alexandra Hering, Matthias Kliegel, Thomas Beer, Gabriele Meyer (Handling Associate Editor: Rebecca Palm)
Social Robot Interventions for People with Dementia: A Systematic Review on Effects and Quality of Reporting
Abstract: Background: Using non-pharmacological interventions is a current approach in dementia care to manage responsive behaviors, to maintain functional capacity, and to reduce emotional stress. Novel technologies such as social robot interventions might be useful to engage people with dementia in activities and interactions as well as to improve their cognitive, emotional, and physical status. Objective: Assessing the effects and the quality of reporting of social robot interventions for people with dementia. Methods: In our systematic review, we included quasi-experimental and experimental studies published in English, French, or German, irrespective of publication year. Searching CINAHL, Cochrane Library, MEDLINE, PsycINFO, and Web of Science Core Collection was supplemented by citation tracking and free web searching. To assess the methodological quality of included studies, we used tools provided by the Joanna Briggs Institute. To assess the reporting of the interventions, we applied CReDECI 2 and TIDieR. Results: We identified sixteen studies published between 2012 and 2018, including two to 415 participants with mostly non-defined type of dementia. Eight studies had an experimental design. The predominant robot types were pet robots (i.e., PARO). Most studies addressed behavioral, emotion-related, and functional outcomes with beneficial, non-beneficial, and mixed results. Predominantly, cognitive outcomes were not improved. Overall, studies were of moderate methodological quality. Conclusion: Heterogeneous populations, intervention characteristics, and measured outcomes make it difficult to generalize the results with regard to clinical practice. The impact of social robot interventions on behavioral, emotion-related, and functional outcomes should therefore be assessed considering the severity of dementia and intervention characteristics.

Pages 793-806
Wenzhe Wu, Inhan Lee, Heidi Spratt, Xiang Fang, Xiaoyong Bao
tRNA-Derived Fragments in Alzheimer’s Disease: Implications for New Disease Biomarkers and Neuropathological Mechanisms
Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia caused by irreversible neurodegeneration, with the onset mechanisms elusive. tRNA-derived RNA fragments (tRFs), a recently discovered family of small non-coding RNAs (sncRNAs), have been found to associate with many human diseases, including infectious, metabolic, and neurological diseases. However, whether tRFs play a role in human AD development is not known. Objective: This study aimed to explore whether tRFs are involved in human AD. Methods: Thirty-four postmortem human hippocampus samples were used. The expression of Drosha, Dicer, and angiogenin (ANG), three ribonucleases responsible for the biogenesis of sncRNAs, was determined by qRT-PCR and western blot. The tRFs in the hippocampus was detected by qRT-PCR or northern blot. We also used qRT-PCR to quantify NOP2/Sun RNA methyltransferase 2 (NSun2) and polyadenylation factor I subunit 1 (CLP1), two tRNA modification enzymes. Results: tRFs derived from a subset of tRNAs are significantly altered in the hippocampus of AD patients. The expression change of some tRFs showed age- and disease stage-dependent. ANG is significantly enhanced in AD, suggesting its role in inducing tRFs in AD. The expression of NSun2 in AD patients younger than 65 was significantly decreased. According to a previous report supporting NSun2-mediated tRNA methylation modification making tRNA less susceptible to ANG-mediated cleavage, our results suggested that the decrease in NSun2 may make tRNAs less methylated and subsequently enhanced tRF production from ANG-mediated tRNA cleavage. Conclusion: Our studies demonstrated for the first time the involvement of tRFs in human AD.

Pages 807-817
Jing Yuan*, Nancy Maserejian*, Yulin Liu, Sherral Devine, Cai Gillis, Joseph Massaro, Rhoda Au (Handling Associate Editor: Mark Bondi) *These authors contributed equally to this work.
Severity Distribution of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in the Framingham Heart Study
Abstract: Background: Studies providing Alzheimer’s disease (AD) prevalence data have largely neglected to characterize the proportion of AD that is mild, moderate, or severe. Estimates of the severity distribution along the AD continuum, including the mild cognitive impairment (MCI) stage, are important to plan research and allocate future resources, particularly resources targeted at particular stages of disease. Objective: To characterize the distribution of severity of AD dementia and MCI among prevalent cases in the population-based Framingham Heart Study. Methods: Participants (aged 50-94) with prevalent MCI or AD dementia clinical syndrome were cross-sectionally selected from three time-windows of the population-based Framingham Heart Study in 2004-2005 (n=381), 2006-2007 (n=422), and 2008-2009 (n=389). Summary estimates of the severity distribution were achieved by pooling results across time-windows. Diagnosis and severity were assessed by consensus dementia review. MCI-progressive was determined if the participant had documented progression to AD dementia clinical syndrome using longitudinal data. Results: Among AD dementia participants, the pooled percentages were 50.4% for mild, 30.3% for moderate, and 19.3% for severe. Among all MCI and AD participants, the pooled percentages were 29.5%, 19.6%, 25.7%, and 45.2% for MCI-not-progressive, MCI-progressive, mild AD dementia, and the combined group of MCI-progressive and mild AD dementia, respectively. Distributions by age and sex were presented. Conclusion: The finding that half of the people living with AD have mild disease underscores the need for research and interventions to slow decline or prevent progression of this burdensome disease.

Pages 819-832
Yi-Wen Bao, Anson C.M. Chau, Patrick Ka-Chun Chiu, Yat Fung Shea, Joseph S.K. Kwan, Felix Hon Wai Chan, Henry Ka-Fung Mak
Heterogeneity of Amyloid Binding in Cognitively Impaired Patients Consecutively Recruited from a Memory Clinic: Evaluating the Utility of Quantitative 18F-Flutemetamol PET-CT in Discrimination of Mild Cognitive Impairment from Alzheimer’s Disease and Other Dementias
Abstract: Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included 13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force.

Pages 833-844
Yang-Yang Wang*, Qian Yan*, Zhen-Ting Huang, Qian Zou, Jing Li, Ming-Hao Yuan, Liang-Qi Wu, Zhi-You Cai *These authors contributed equally to this work.
Ameliorating Ribosylation-Induced Amyloid-β Pathology by Berberine via Inhibiting mTOR/p70S6K Signaling
Abstract: Background: Berberine (BBR) plays a neuroprotective role in the pathogenesis of Alzheimer’s disease (AD), inhibiting amyloid-β (Aβ) production and promoting Aβ clearance. Advanced glycation end products (AGEs) promote Aβ aggregation and tau hyperphosphorylation. The activation of mTOR signaling occurring at the early stage of AD has a prominent impact on the Aβ production. This work focused on whether BBR regulates the production and clearance of ribosylation-induced Aβ pathology via inhibiting mTOR signaling. Objective: To explore whether BBR ameliorates ribosylation-induced Aβ pathology in APP/PS1 mice. Methods: Western blot and immunofluorescence staining were used to detect the related proteins of the mammalian target of Rapamycin (mTOR) signaling pathway and autophagy, as well as the related kinases of Aβ generation and clearance. Tissue sections and Immunofluorescence staining were used to observe Aβ42 in APP/PS1 mice hippocampal. Morris water maze test was used to measure the spatial learning and memory of APP/PS1 mice. Results: BBR improves spatial learning and memory of APP/PS1 mice. BBR limits the activation of mTOR/p70S6K signaling pathway and enhances autophagy process. BBR reduces the activity of BACE1 and γ-secretase induced by D-ribose, and enhances Aβ-degrading enzymes and Neprilysin, and inhibits the expression of Aβ in APP/PS1 mice. Conclusion: BBR ameliorates ribosylation-induced Aβ pathology via inhibiting mTOR/p70S6K signaling and improves spatial learning and memory of the APP/PS1 mice.

Pages 845-861
Francisco Javier Balea-Fernandez, Beatriz Martinez-Vega, Samuel Ortega, Himar Fabelo, Raquel Leon, Gustavo M. Callico, Cristina Bibao-Sieyro
Analysis of Risk Factors in Dementia Through Machine Learning
Abstract: Background: Sociodemographic data indicate the progressive increase in life expectancy and the prevalence of Alzheimer's disease (AD). AD is raised as one of the greatest public health problems. Its etiology is twofold: on the one hand, non-modifiable factors and on the other, modifiable. Objective: This study aims to develop a processing framework based on machine learning (ML) and optimization algorithms to study sociodemographic, clinical, and analytical variables, selecting the best combination among them for an accurate discrimination between controls and subjects with major neurocognitive disorder (MNCD). Methods: This research is based on an observational-analytical design. Two research groups were established: MNCD group (n = 46) and control group (n = 38). ML and optimization algorithms were employed to automatically diagnose MNCD. Results: Twelve out of 37 variables were identified in the validation set as the most relevant for MNCD diagnosis. Sensitivity of 100% and specificity of 71% were achieved using a Random Forest classifier. Conclusion: ML is a potential tool for automatic prediction of MNCD which can be applied to relatively small preclinical and clinical data sets. These results can be interpreted to support the influence of the environment on the development of AD.

Pages 863-874
Carmen Lage, Andrea González-Suárez, María Puerto Alcalde-Hierro, María Isabel Sampedro-González, María Ángeles Villanueva-Eguaras, Manuel Rubén Sánchez-Crespo, Catherine Widmann, Frederic Brosseron, Ana Pozueta, Sara López-García, María García-Martínez, Martha Kazimierczak, María Bravo-González, Andrea Fernández-Rodríguez, Marta Drake-Pérez, Juan Irure-Ventura, Marcos López-Hoyos, Eloy Rodríguez-Rodríguez, Michael T Heneka, Pascual Sánchez-Juan (Handling Associate Editor: Carla Abdelnour)
Major Surgery Affects Memory in Individuals with Cerebral Amyloid-β Pathology
Abstract: Background: Major surgery has been associated with perioperative neurocognitive disorders (PND), but the contributing factors and long-term prognosis are uncertain. We hypothesize that preclinical Alzheimer's disease (AD) might predispose to cognitive deterioration after surgery. Objective: To analyze the effect of amyloid-β on the cognitive trajectory after orthopedic surgery in a sample of non-demented subjects. Methods: Non-demented individuals older than 65 years that were on the waiting list for orthopedic surgery with spinal anesthesia underwent a neuropsychological assessment before and after surgery. During surgery, cerebrospinal fluid samples were obtained to determine AD biomarkers. Results: Cumulative incidence of PND was 55.2% during a mean follow-up of nine months. The most affected cognitive domains were executive function and constructional praxis. The presence of abnormal levels of amyloid-β was associated to a postoperative impairment in verbal and visual memory tests. According to their AD biomarker profile, participants were categorized as either Amyloid Positive (A+) or Amyloid Negative (A-). The incidence of PND did not differ between both groups. The A- group showed a tendency similar to the global sample, worsening in executive function tests and improving on memory scales due to practice effects. In contrast, the A+ group showed a notable worsening on memory performance. Conclusion: Our findings support the hypothesis that surgery may promote or accelerate memory decline in cognitively asymptomatic subjects with brain amyloid-β deposits.

Pages 875-893
Lilit Gabrielyan, Honghui Liang, Artem Minalyan, Asa Hatami, Varghese John, Lixin Wang
Behavioral Deficits and Brain α-Synuclein and Phosphorylated Serine-129 α-Synuclein in Male and Female Mice Overexpressing Human α-Synuclein
Abstract: Background: Alpha-synuclein (α-syn) is a molecule involved in pathology of Parkinson’s disease, and 90% of α-syn in Lewy bodies is phosphorylated at serine 129 (pS129 α-syn). Objective: To assess motor and non-motor behaviors in male and female mice overexpressing human α-syn under Thy1 promoter (Thy1-α-syn) and wild type (wt) littermates. Methods: Motor and non-motor behaviors brain human α-syn levels by ELISA, and mapped α-syn and pS129 α-syn in the brain by immunohistochemistry. Results: Male and female wt littermates did not show differences in the behavioral tests. Male Thy1-α-syn mice displayed more severe impairments than female counterparts in cotton nesting, pole tests, adhesive removal, finding buried food, and marble burying. Concentrations of human α-syn in the olfactory regions, cortex, nigrostriatal system, and dorsal medulla were significantly increased in Thy1-α-syn mice, higher in males than females. Immunoreactivity of α-syn was not simply increased in Thy1-α-syn mice but had altered localization in somas and fibers in a few brain areas. Abundant pS129 α-syn existed in many brain areas of Thy1-α-syn mice, while there was none or only a small amount in a few brain regions of wt mice. The substantia nigra, olfactory regions, amygdala, lateral parabrachial nucleus, and dorsal vagal complex displayed different distribution patterns between wt and transgenic mice, but not between sexes. Conclusion: The severer abnormal behaviors in male than female Thy1-α-syn mice may be related to higher brain levels of human α-syn, in the absence of sex differences in the altered brain immunoreactivity patterns of α-syn and pS129 α-syn.

Pages 895-903
Pratishtha Chatterjee, Anne M. Fagan, Chengjie Xiong, Matthew McKay, Atul Bhatnagar, Yunqi Wu, Abhay K. Singh, Kevin Taddei, Ian Martins, Samantha L. Gardener, Mark P. Molloy, Gerhard Multhaup, Colin L. Masters, Peter R. Schofield, Tammie L.S. Benzinger, John C. Morris, Randall J. Bateman, Steven M. Greenberg, Marieke J.H. Wermer, Mark A. van Buchem, Hamid R. Sohrabi, Ralph N. Martins and Dominantly Inherited Alzheimer Network
Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations
Abstract: Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n=9) and non-carriers (D-CAA NCs, n=8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in the D-CAA MCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p<0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in the D-CAA MCs compared to the D-CAA NCs (p<0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p<0.01). Spermidine was also observed to correlate with CSF Aβ40 (rs=0.621, p=0.024), CSF Aβ42 (rs=0.714, p=0.006), and brain Aβ load (rs=-0.527, p=0.030). Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

Pages 905-916
Minh Tuan Hoang, Ingemar Kåreholt, Mia von Euler, Lena von Koch, Maria Eriksdotter, Sara Garcia-Ptacek
Satisfaction with Stroke Care Among Patients with Alzheimer’s and Other Dementias: A Swedish Register-Based Study
Abstract: Background: Patient dissatisfaction with stroke care is associated with poor self-rated health and unmet care needs. Dementia patients’ satisfaction with stroke care is understudied. Objective: To compare satisfaction with stroke care in patients with and without dementia. Methods: This longitudinal cohort study included 5,932 dementia patients (2007-2017) who suffered a first stroke after dementia diagnosis and 39,457 non-dementia stroke patients (2007-2017). Data were retrieved by linking the Swedish Stroke Register, the Swedish Dementia Register, the Swedish National Patient Register, and the Swedish Prescribed Drug Register. The association between dementia and satisfaction was analyzed with ordinal logistic regression. Results: When dementia patients answered themselves, they reported significantly lower odds of satisfaction with acute stroke care (OR: 0.71; 95% CI: 0.60-0.85), healthcare staff’s attitude (OR: 0.79; 95% CI: 0.66-0.96), communication with doctors (OR: 0.78; 95% CI: 0.66-0.92), stroke information (OR: 0.62; 95% CI: 0.52-0.74); but not regarding inpatient rehabilitation (OR: 0.93; 95% CI: 0.75-1.16), or outpatient rehabilitation (OR: 0.93; 95% CI: 0.73-1.18). When patients answered with caregivers’ help, the association between dementia status and satisfaction remained significant in all items. Subgroup analyses showed that patients with Alzheimer’s disease and mixed dementia reported lower odds of satisfaction with acute care and healthcare staff’s attitude when they answered themselves. Conclusion: Patients with dementia reported lower satisfaction with stroke care, revealing unfulfilled care needs among dementia patients, which are possibly due to different (or less) care, or because dementia patients require adaptations to standard care.

Pages 917-927
Krista Tromp*, Marthe Smedinga*, Edo Richard, Marieke Perry, Maartje H.N. Schermer *These authors contributed equally to this work.
Views on Early Diagnosis of Alzheimer’s Disease Among Dutch Physicians: A Qualitative Interview Study
Abstract: Background: Hope for future treatments to prevent or slow down dementia motivates researchers to strive for ever-earlier diagnoses of Alzheimer’s disease (AD) based on biomarkers, even before symptoms occur. But is a biomarker-based early diagnosis desirable in clinical practice? Objective: This study explores the ethical considerations that shape current clinical practice regarding early AD diagnostics and the use of biomarkers. Methods: In this qualitative study, Dutch physicians were interviewed. Topics included physicians’ views concerning early AD diagnosis in persons with no or mild cognitive impairment, physicians’ considerations regarding current and expected future practices of early AD diagnosis, the use of biomarkers, and the use of the concepts preclinical and prodromal AD. We analyzed the transcripts using directed content analysis. Results: 15 general practitioners, neurologists, and geriatricians in the Netherlands were interviewed. Most of them interpreted an early AD diagnosis with an early diagnosis of dementia. We identified six clusters of considerations sometimes in favor but most often against pursuing an early AD diagnosis in people with no or mild cognitive impairment that influence physicians’ diagnostic decision-making: preferences and characteristics of persons, test characteristics, impact on care, type of setting, disease concepts, and issues on a societal level. Conclusion: The discussion concerning an early AD diagnosis based on biomarkers which is widely held in the scientific field, has not entered clinical practice structurally. A biomarker-based early diagnosis does not fit within Dutch physicians’ views on what good care for people with no, subjective, or mild cognitive impairment should entail.