Volume 80, Number 1, IN PRESS

Review
David A. Loeffler (Handling Associate Editor: Suzanne Tyas)
Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer’s Disease
Abstract: There is an extensive literature relating to factors associated with the development of Alzheimer’s disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ε4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.

Review
Luigi Ferini-Strambi, Michael Hensley, Maria Salsone
Decoding Causal Links Between Sleep Apnea and Alzheimer’s Disease
Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two chronic conditions.

Review
Jessica L. Dennison*, Natalie R. Ricciardi*, Ines Lohse, Claude-Henry Volmar, Claes Wahlestedt *These authors contributed equally to this work.
Sexual Dimorphism in the 3xTg-AD Mouse Model and Its Impact on Pre-Clinical Research
Abstract: Female sex is a leading risk factor for developing Alzheimer’s disease (AD). Sexual dimorphism in AD is gaining attention as clinical data show that women are not only more likely to develop AD but also to experience worse pathology and faster cognitive decline. Pre-clinical AD research in animal models often neglects to address sexual dimorphism in evaluation of behavioral or molecular characteristics and outcomes. This can compromise its translation to a clinical setting. The triple-transgenic AD mouse model (3xTg-AD) is a commonly used but unique AD model because it exhibits both amyloid and tau pathology, essential features of the human AD phenotype. Mounting evidence has revealed important sexually dimorphic characteristics of this animal model that have yet to be reviewed and thus, are often overlooked in studies using the 3xTg-AD model. In this review we conduct a thorough analysis of reports of sexual dimorphism in the 3xTg-AD model including findings of molecular, behavioral, and longevity-related sex differences in original research articles through August 2020. Importantly, we find results to be inconsistent, and that strain source and differing methodologies are major contributors to lack of consensus regarding traits of each sex. We first touch on the nature of sexual dimorphism in clinical AD, followed by a brief summary of sexual dimorphism in other major AD murine models before discussing the 3xTg-AD model in depth. We conclude by offering four suggestions to help unify pre-clinical mouse model AD research inspired by the NIH expectations for considering sex as a biological variable.

Review
Yu-si Chen*, Kai Shu*, Hui-cong Kang *These authors contributed equally to this work.
Deep Brain Stimulation in Alzheimer’s Disease: Targeting the Nucleus Basalis of Meynert
Abstract: Alzheimer’s disease (AD) is becoming a prevalent disease in the elderly population. Past decades have witnessed the development of drug therapies with varying targets. However, all drugs with a single molecular target fail to reverse or ameliorate AD progression, which ultimately results in cortical and subcortical network dysregulation. Deep brain stimulation (DBS) has been proven effective for the treatment of Parkinson’s disease, essential tremor, and other neurological diseases. As such, DBS has also been gradually acknowledged as a potential therapy for AD. The current review focuses on DBS of the nucleus basalis of Meynert (NBM). As a critical component of the cerebral cholinergic system and the Papez circuit in the basal ganglia, the NBM plays an indispensable role in the subcortical regulation of memory, attention, and arousal state, which makes the NBM a promising target for modulation of neural network dysfunction and AD treatment. We summarized the intricate projection relations and functionality of the NBM, current approaches for stereotactic localization and evaluation of the NBM, and the therapeutic effects of NBM-DBS both in patients and animal models. Furthermore, the current shortcomings of NBM-DBS, such as variations in cortical blood flow, increased temperature in the target area, and stimulation-related neural damage, were presented.

Short Communication
Fan Chen, Yan Zhang, Longcai Wang, Tao Wang, Zhifa Han, Haihua Zhang, Shan Gao, Yang Hu, Guiyou Liu
PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis
Abstract: We aimed to evaluate the association of PLCG2 rs72824905 variant with Alzheimer’s disease (AD) and multiple sclerosis (MS) using large-scale genetic association study datasets. We selected 50,024 AD cases and 467,330 controls, and 32,367 MS cases and 36,012 controls. We found moderate heterogeneity of rs72824905 in different studies. We found significant association between rs72824905 G allele and reduced AD risk (OR = 0.66, 95% CI 0.59-0.74, p = 5.91E-14). Importantly, rs72824905 G allele could also significantly reduce the risk of MS with OR = 0.94, p = 3.63E-05. Hence, the effects of rs72824905 on AD and MS are consistent.

Jing Zhou, Rod L. Walker, Shelly L. Gray, Zachary A. Marcum, Douglas Barthold, James D. Bowen, Wayne McCormick, Susan M. McCurry, Eric B. Larson*, Paul K. Crane* *These authors contributed equally to this work.
Glucose-Dementia Association Is Consistent Over Blood Pressure/Antihypertensive Groups
Abstract: Background: Higher glucose levels are associated with dementia risk in people with and without diabetes. However, little is known about how this association might vary by hypertension status and antihypertensive treatment. Most studies on modifiable dementia risk factors consider each factor in isolation. Objective: To test the hypothesis that hypertension and antihypertensive treatments may modify associations between glucose levels and dementia. Methods: Analyses of data generated from a research study and clinical care of participants from a prospective cohort of dementia-free older adults, including glucose measures, diabetes and antihypertensive treatments, and blood pressure data. We defined groups based on blood pressure (hypertensive versus not, 140/90 mmHg versus <140/90 mmHg) and antihypertensive treatment intensity (0, 1, or 2 classes of antihypertensives). We used Bayesian joint models to jointly model longitudinal exposure and time to event data. Results: A total of 3,056 participants without diabetes treatment and 480 with diabetes treatment were included (mean age at baseline, 75.1 years; mean 7.5 years of follow-up). Higher glucose levels were associated with greater dementia risk among people without and with treated diabetes. Hazard ratios for dementia were similar across all blood pressure/antihypertensive treatment groups (omnibus p = 0.82 for people without and p=0.59 for people with treated diabetes). Conclusion: Hypertension and antihypertensive treatments do not appear to affect the association between glucose and dementia risk in this population-based longitudinal cohort study of community-dwelling older adults. Future studies are needed to examine this question in midlife and by specific antihypertensive treatments.

Elizabeth Dao, Roger Tam, Ging-Yuek R. Hsiung, Lisanne ten Brinke, Rachel Crockett, Cindy K. Barha, Youngjin Yoo, Walid Al Keridy, Stephanie H. Doherty, Cornelia Laule, Alex L. MacKay, Teresa Liu-Ambrose (Handling Associate Editor: Michele Callisaya)
Exploring the Contribution of Myelin Content in Normal Appearing White Matter to Cognitive Outcomes in Cerebral Small Vessel Disease
Abstract: Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood. Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD. Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤ 0.05. Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β = -0.29, p = 0.037) and poorer working memory (β = 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132). Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function.

Eric. E. Smith, Zahinoor Ismail
Mortality Risk Models for Persons with Dementia: A Systematic Review
Abstract: Background: Persons with dementia have higher mortality than the general population. Objective, standardized predictions of mortality risk in persons with dementia could help with planning resources for care close to the end of life. Objective: To systematically review prediction models for risk of death in persons with dementia. Methods: The Medline and PsycInfo databases were searched on November 29, 2020, for prediction models estimating the risk of death in persons with dementia. Study quality was assessed using the Prediction model Risk Of Bias ASsessment Tool. Results: The literature search identified 2,828 studies, of which 18 were included. These studies described 16 different prediction models with c statistics mostly ranging from 0.67 to 0.79. Five models were externally validated, of which four were applicable. There were two models that were both applicable and had reasonably low risk of bias. One model predicted risk of death at six months in persons with advanced dementia residing in a nursing home. The other predicted risk of death at three years in persons seen in primary care practice or a dementia specialty clinic, derived from a nationwide registry in Sweden but not externally validated. Conclusions: Valid, applicable models with low risk of bias were found in two settings: advanced dementia in a nursing home and outpatient practices. The outpatient model requires external validation. Better models are needed for persons with mild to moderate dementia in nursing homes, a common demographic. These models may be useful for educating persons living with dementia and care partners and directing resources for end of life care.

Lília Jorge, Ricardo Martins, Nádia Canário, Carolina Xavier, Antero Abrunhosa, Isabel Santana, Miguel Castelo-Branco (Handling Associate Editor: Josephine Barnes)
Investigating the Spatial Associations Between Amyloid-β Deposition, Grey Matter Volume, and Neuroinflammation in Alzheimer's Disease
Abstract: Background: It has been proposed that amyloid-β (Aβ) plays a causal role in Alzheimer’s disease (AD) by triggering a series of pathologic events—possibly including neuroinflammation—which culminate in progressive brain atrophy. However, the interplay between the two pathological molecular events and how both are associated with neurodegeneration is still unclear. Objective: We aimed to estimate the spatial inter-relationship between neurodegeneration, neuroinflammation and Aβ deposition in a cohort of in 20 mild AD patients and 17 healthy controls. Methods: We resorted to magnetic resonance imaging to measure cortical atrophy, using the radiotracer 11C-PK11195 PET to measure neuroinflammation levels and 11C-PiB PET to assess Aβ levels. Between-group comparisons were computed to explore AD-related changes in the three types of markers. To examine the effects of each one of the molecular pathologic mechanisms on neurodegeneration we computed: 1) ANCOVAs with the anatomic data, controlling for radiotracer uptake differences between groups and 2) voxel-based multiple regression analysis between-modalities. In addition, associations in anatomically defined regions of interests were also investigated. Results: We found significant differences between AD and controls in the levels of atrophy, neuroinflammation, and Aβ deposition. Associations between Aβ aggregation and brain atrophy were detected in AD in a widely distributed pattern, whereas associations between microglia activation and structural measures of neurodegeneration were restricted to few anatomically regions. Conclusion: In summary, Aβ deposition, as opposed to neuroinflammation, was more associated with cortical atrophy, suggesting a prominent role of Aβ in neurodegeneration at a mild stage of the AD.

Alan S. Plotzker, Rachel L. Henson, Anne M. Fagan, John C. Morris, Gregory S. Day
Clinical and Paraclinical Measures Associated with Outcome in Cerebral Amyloid Angiopathy with Related Inflammation
Abstract: Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable. Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone. Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513). Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p=0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p=0.04), or lower CSF Aβ40 at presentation (rho=-0.83; p=0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p=0.03) or higher late ARIA-E scores (rho=0.70; p=0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p=0.66). Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.

Sung Hoon Kang*, Bo Kyoung Cheon*, Ji-Sun Kim, Hyemin Jang, Hee Jin Kim, Kyung Won Park, Young Noh, Jin San Lee, Byoung Seok Ye, Duk L. Na, Hyejoo Lee**, Sang Won Seo** *,**These authors contributed equally to this work.
Machine Learning for the Prediction of Amyloid Positivity in Amnestic Mild Cognitive Impairment
Abstract: Background: Amyloid (Aβ) evaluation in amnestic mild cognitive impairment (aMCI) patients is important for predicting conversion to Alzheimer’s disease. However, Aβ evaluation through amyloid positron emission tomography (PET) is limited due to high cost and safety issues. Objective: We therefore aimed to develop and validate prediction models of Aβ positivity for aMCI using optimal interpretable machine learning (ML) approaches utilizing multimodal markers. Methods: We recruited 529 aMCI patients from multiple centers who underwent Aβ PET. We trained ML algorithms using a training cohort (324 aMCI from Samsung medical center) with two-phase modelling: model 1 included age, gender, education, diabetes, hypertension, apolipoprotein E genotype, and neuropsychological test scores; model 2 included the same variables as model 1 with additional MRI features. We used four-fold cross-validation during the modelling and evaluated the models on an external validation cohort (187 aMCI from the other centers). Results: Model 1 showed good accuracy (area under the receiver operating characteristic curve [AUROC] 0.837) in cross-validation, and fair accuracy (AUROC 0.765) in external validation. Model 2 led to improvement in the prediction performance with good accuracy (AUROC 0.892) in cross validation compared to model 1. Apolipoprotein E genotype, delayed recall task scores, and interaction between cortical thickness in the temporal region and hippocampal volume were the most important predictors of Aβ positivity. Conclusion: Our results suggest that ML models are effective in predicting Aβ positivity at the individual level and could help the biomarker-guided diagnosis of prodromal AD.

Masaki Nakano, Yachiyo Mitsuishi, Lei Liu, Naoki Watanabe, Emi Hibino, Saori Hata, Takashi Saito, Takaomi C. Saido, Shigeo Murayama, Kensaku Kasuga, Takeshi Ikeuchi, Toshiharu Suzuki, Masaki Nishimura (Handling Associate Editor: Shun Shimohama)
Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations
Abstract: Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

Ellen Grober, Qi Qi, Lynn Kuo, Jason Hassenstab, Richard J. Perrin, Richard B. Lipton
The Free and Cued Selective Reminding Test Predicts Braak Stage
Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To identify clinical markers that predict pathology, we evaluated the relationships of the picture version of the Free and Cued Selective Reminding Test (pFCSRT+IR), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to Braak stage. Methods: 315 cases from the clinicopathologic series at the Knight Alzheimer’s Disease Research Center were classified according to Braak stage. Boxplots of each predictor were compared to identify the earliest stage at which decline was observed and ordinal logistic regression was used to predict Braak stage. Results: Looking at the assessment closest to death, free recall scores were lower in individuals at Braak stage III versus Braak stages 0 and I (combined) while MMSE and CDR-SB scores for individuals did not differ from Braak stages 0/I until Braak stage IV. The sum of free recall and total recall scores independently predicted Braak stage and had higher predictive validity than MMSE and CDR-SB in models including all three. Conclusion: pFCSRT+IR+IR scores may be more sensitive to early pathological changes than either the CDR-SB or the MMSE.

Ellen Grober, Qi Qi, Lynn Kuo, Jason Hassenstab, Richard J. Perrin, Richard B. Lipton
Stages of Objective Memory Impairment Predict Alzheimer’s Disease Neuropathology: Comparison with the Clinical Dementia Rating Scale–Sum of Boxes
Abstract: Background: The ultimate validation of a clinical marker for Alzheimer’s disease (AD) is its association with AD neuropathology. Objective: To examine how well the Stages of Objective Memory Impairment (SOMI) system predicts intermediate/high AD neuropathologic change and extent of neurofibrillary tangle (NFT) pathology defined by Braak stage, in comparison to the Clinical Dementia Rating (CDR) Scale sum of boxes (CDR-SB). Methods: 251 well-characterized participants from the Knight ADRC clinicopathologic series were classified into SOMI stage at their last assessment prior to death using the free recall and total recall scores from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT+ IR). Logistic regression models assessed the predictive validity of SOMI and CDR-SB for intermediate/high AD neuropathologic change. Receiver operating characteristics (ROC) analysis evaluated the discriminative validity of SOMI and CDR-SB for AD pathology. Ordinal logistic regression was used to predict Braak stage using SOMI and CDR-SB in separate and joint models. Results: The diagnostic accuracy of SOMI for AD diagnosis was similar to that of the CDR-SB (AUC: 85% versus 83%). In separate models, both SOMI and CDR-SB predicted Braak stage. In a joint model SOMI remained a significant predictor of Braak stage but CDR-SB did not. Conclusion: SOMI provides a neuropathologically validated staging system for episodic memory impairment in the AD continuum and should be useful in predicting tau positivity based on its association with Braak stage.

Jaehyun Kim, Tae Hyon Ha, Kiwon Kim, Eun-Mi Lee, Hyekyeong Kim, Doh Kwan Kim, Hong-Hee Won, Matthew Lewis, Hyewon Lee*, Woojae Myung* (Handling Associate Editor: Kaarin Anstey) *These authors contributed equally to this work.
Atypical Antipsychotics Augmentation in Patients with Depressive Disorder and Risk of Subsequent Dementia: A Nationwide Population-Based Cohort Study
Abstract: Background: While atypical antipsychotic medications are widely used for treating depressive disorders, their long-term effects on the risk of subsequent dementia have not been studied adequately. Objective: To investigate whether the risk of dementia differs according to the use of atypical antipsychotic drugs and compare the effects of antipsychotic agents on dementia risk in individuals with late-life depressive disorders. Methods: A nationwide population-based retrospective cohort study was conducted using data from the National Health Insurance Service—Senior Cohort of South Korea. Atypical antipsychotic dosages were standardized using a defined daily dose, and the cumulative dosage was calculated. Participants were observed from January 2008 to December 2015. Cox proportional hazard regression analysis was used to estimate the hazard ratios. Results: The cohort included 43,788 elderly adults with depressive disorders: 9,901 participants (22.6%) were diagnosed with dementia. Findings showed that atypical antipsychotics were prescribed to 1,967 participants (4.5%). Compared with non-users, users of atypical antipsychotics experienced a significantly higher risk for dementia with an adjusted hazard ratio (aHR) of 1.541 (95% confidence interval [CI], 1.415-1.678). A cumulative dose-response relationship was observed (test for trend, p<0.0001). Among atypical antipsychotics, risperidone displayed the highest risk for dementia (aHR 1.767, [95% CI, 1.555-2.009]). Conclusion: In this study of elderly individuals with depressive disorders, atypical antipsychotic use was associated with a significantly higher risk of subsequent dementia. Healthcare professionals should be aware of this potential long-term risk. A limitation that should be mentioned is that we could not exclude patients with bipolar depression.

Ana Macedo, Carlos Gómez, Miguel Ângelo Rebelo, Jesús Poza, Iva Gomes, Sandra Martins, Aarón Maturana-Candelas, Víctor Gutiérrez-de Pablo, Luis Durães, Patrícia Sousa, Manuel Figueruelo, Maria Rodriguez, Carmen Pita, Miguel Arenas, Luís Alvarez, Roberto Hornero, Alexandra M. Lopes, Nádia Pinto (Handling Associate Editor: Christian Musaeus)
Risk Variants in Three Alzheimer’s Disease Genes Show Association with EEG Endophenotypes
Abstract: Background: Dementia due to Alzheimer’s disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. Objective: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2β, SORL1, TOMM40, GSK3β, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. Methods: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. Results: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ε4 presence. Conclusion: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

Miles Welstead, Michelle Luciano, Graciela Muniz-Terrera, Stina Saunders, Donncha S. Mullin, Tom C. Russ
Predictors of Mild Cognitive Impairment Stability, Progression, or Reversion in the Lothian Birth Cohort 1936
Abstract: Background: Mild cognitive impairment (MCI) describes a borderland between healthy cognition and dementia. Progression to and reversion from MCI is relatively common but more research is required to understand the factors affecting this fluidity and improve clinical care interventions. Objective: We explore these transitions in MCI status and their predictive factors over a six-year period in a highly-phenotyped longitudinal study, the Lothian Birth Cohort 1936. Methods: MCI status was derived in the LBC1936 at ages 76 (n=567) and 82 years (n=341) using NIA-AA diagnostic guidelines. Progressions and reversions between healthy cognition and MCI over the follow-up period were assessed. Multinomial logistic regression assessed the effect of various predictors on the likelihood of progressing, reverting, or maintaining cognitive status. Results: Of the 292 participants who completed both time points, 41 (14%) participants had MCI at T1 and 56 (19%) at T2. Over the follow-up period, 74% remained cognitively healthy, 12% transitioned to MCI, 7% reverted to healthy cognition, and 7% maintained their baseline MCI status. Findings indicated that membership of these transition groups was affected by age, cardiovascular disease, and number of depressive symptoms. Conclusion: Findings that higher baseline depressive symptoms increase the likelihood of reverting from MCI to healthy cognition indicate that there may be an important role for the treatment of depression for those with MCI. However, further research is required to identify prevention strategies for those at high risk of MCI and inform effective interventions that increase the likelihood of reversion to, and maintenance of healthy cognition.

Fang Yu, David M. Vock, Lin Zhang, Dereck Salisbury, Nathaniel W. Nelson, Lisa S. Chow, Glenn Smith, Terry R. Barclay, Maurice Dysken, Jean F. Wyman
Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial
Abstract: Background: Aerobic exercise has shown inconsistent cognitive effects in older adults with Alzheimer’s disease (AD) dementia. Objective: To examine the immediate and longitudinal effects of 6-month cycling on cognition in older adults with AD dementia. Methods: This randomized controlled trial randomized 96 participants (64 to cycling and 32 to stretching for six months) and followed them for another six months. The intervention was supervised, moderate-intensity cycling for 20-50 minutes, 3 times a week for six months. The control was light-intensity stretching. Cognition was assessed at baseline, 3, 6, 9, and 12 months using the AD Assessment Scale-Cognition (ADAS-Cog). Discrete cognitive domains were measured using the AD Uniform Data Set battery. Results: The participants were 77.4±6.8 years old with 15.6±2.9 years of education, and 55% were male. The 6-month change in ADAS-Cog was 1.0±4.6 (cycling) and 0.1±4.1 (stretching), which were both significantly less than the natural 3.2±6.3-point increase observed naturally with disease progression. The 12-month change was 2.4±5.2 (cycling) and 2.2±5.7 (control). ADAS-Cog did not differ between groups at 6 (p=0.386) and 12 months (p=0.856). There were no differences in the 12-month rate of change in ADAS-Cog (0.192 versus 0.197, p=0.967), memory (-0.012 versus -0.019, p=0.373), executive function (-0.020 versus -0.012, p=0.383), attention (-0.035 versus -0.033, p=0.908), or language (-0.028 versus -0.026, p=0.756). Conclusion: Exercise may reduce decline in global cognition in older adults with mild-to-moderate AD dementia. Aerobic exercise did not show superior cognitive effects to stretching in our pilot trial, possibly due to the lack of power.

Zhongmeng Lai, Jia Min, Jun Li, Weiran Shan, Weifeng Yu, Zhiyi Zuo
Surgery Trauma Severity but not Anesthesia Length Contributes to Postoperative Cognitive Dysfunction in Mice
Abstract: Background: Perioperative, modifiable factors contributing to perioperative neurocognitive disorders (PND) have not been clearly defined. Objective: To determine the contribution of anesthesia lengths and the degrees of surgical trauma to PND and neuroinflammation, a critical process for PND. Methods: Three-month-old C57BL/6J mice were subjected to 2-h or 6-h isoflurane anesthesia plus a 5-min or 15-min left common carotid artery exposure (surgery) in a factorial design (two factors: anesthesia with two levels and surgery with three levels). Their learning and memory were tested by Barnes maze and novel object recognition paradigms. Blood, spleen, and hippocampus were harvested for measuring interleukin (IL)-6 and IL-1β. Eighteen-month-old C57BL/6J mice (old mice) were subjected to 6-h isoflurane anesthesia or 2-h isoflurane anesthesia plus 15-min surgery and then had learning and memory tested. Results: Three-month-old mice with 15-min surgery (long surgery) under 2-h or 6-h anesthesia performed poorly in the learning and memory tests compared with controls. Anesthesia alone or anesthesia plus 5-min surgery did not affect mouse performance in these tests. Similarly, only mice with long surgery but not mice with other experimental conditions had increased IL-6 and IL-1β in the blood, spleen, and hippocampus and decreased spleen weights. Splenocytes were found in the hippocampus after surgery. Similarly, old mice with long surgery but not the mice with isoflurane anesthesia alone had poor performance in the Barnes maze and novel object recognition tests. Conclusion: Surgical trauma, but not anesthesia, contributes to the development of PND and neuroinflammation. Splenocytes may modulate these processes.

Yu-Chen Chuang, Ming-Jang Chiu, Ta-Fu Chen, Yu-Ling Chang, Ya-Mei Lai, Ting‐Wen Cheng, Mau-Sun Hua
An Exploration of the Own-Age Effect on Facial Emotion Recognition in Normal Elderly People and Individuals with the Preclinical and Demented Alzheimer’s Disease
Abstract: Background: The issue of whether there exists an own-effect on facial recognition in the elderly remains equivocal. Moreover, currently the literature of this issue in pathological aging is little. Objective: Our study was thus to explore the issue in both of healthy older people and patients with AD. Methods: In study 1, 27 older and 31 younger healthy adults were recruited; in study 2, 27 healthy older adults and 80 patients (including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) groups) were recruited. Participants received the Taiwan Facial Emotion Recognition Task (FER Task), and a clinical neuropsychological assessment. Results: No significant differences on the FER test were found among our groups, except for sadness recognition in which our MCI and AD patients’ scores were remarkably lower than their healthy counterparts. The own-age effect was not significantly evident in healthy younger and older adults, except for recognizing neutral photos. Our patients with MCI and AD tended to have the effect, particularly for the sad recognition in which the effect was significantly evident in terms of error features (mislabeling it as anger in younger-face and neutral in older-face photos). Conclusion: Our results displayed no remarkable own-age effect on facial emotional recognition in the healthy elderly (including SCD). However, it did not appear the case for in MCI and AD patients, especially their recognizing those sadness items, suggesting that an inclusion of the FER task particularly involving those items of low-intensity emotion in clinical neuropsychological assessment might be contributory to the early detection of AD-related pathological individuals.

Qi-Shuai Zhuang*, Lei Meng*, Zhe Wang, Liang Shen, Hong-Fang Ji *These authors contributed equally to this work.
Associations Between Obesity and Alzheimer’s Disease: Multiple Bioinformatic Analyses
Abstract: Background: Identifying modifiable risk factors, such as obesity, to lower the prevalence of Alzheimer’s disease (AD) has gained much interest. However, whether the association is causal remains to be evaluated. Objectives: The present study was designed: 1) to make a quantitative assessment of the association between obesity and AD; 2) to validate whether there was a causal association between them; and 3) to provide genetic clues for the association through a network-based analysis. Methods: Two-sample Mendelian randomization (2SMR) analysis, meta-analysis, and protein-protein interaction (PPI) network analysis, were employed. Results: Firstly, the meta-analysis based on 9 studies comprising 6,986,436 subjects indicated that midlife obesity had 33% higher AD odds than controls (OR = 1.33, 95%CI = [1.03, 1.62]), while late-life obesity were inversely associated with AD risk (OR = 0.57, 95%CI = [0.47, 0.68]). Secondly, 2SMR analysis indicated that there was no causal association between them. Thirdly, CARTPT was identified to be shared by the anti-obesity drug targets and AD susceptibility genes. Further PPI network analysis found that CARTPT interacted with CD33, a strong genetic locus linked to AD. Finally, 2SMR analysis showed that CNR1 could be a protective factor for AD. Conclusion: Multiple bioinformatic analyses indicated that midlife obesity might increase the risk of AD, while current evidence indicated that there was no causal association between them. Further, CARTPT might be an important factor linking the two disease conditions. It could help to better understand the mechanisms underlying the associations between obesity and AD.

Julia Hartmann*, Carola Roßmeier*, Lina Riedl, Bianca Dorn, Julia Fischer, Till Slawik, Mareike Fleischhaker, Florentine Hartmann, Silvia Egert-Schwender, Victoria Kehl, Bernhard Haller, Helga Schneider-Schelte, Andreas Dinkel, Ralf J. Jox, Janine Diehl-Schmid *These authors contributed equally to this work.
Quality of Life in Advanced Dementia with Late Onset, Young Onset, and Very Young Onset
Abstract: Background: Advanced stages of dementia are characterized by severe cognitive and physical impairment. It has not yet been investigated whether persons with young onset dementia (YOD) and late onset dementia (LOD) differ in advanced disease stages. Objectives: To compare quality of life (QoL) between persons with advanced YOD and LOD; to explore the determinants of QoL; to investigate whether YOD and LOD differ with regard to symptoms and care. Methods: The study was performed in the context of EPYLOGE (IssuEs in Palliative care for persons in advanced and terminal stages of YOD and LOD in Germany). Persons with advanced dementia (PWAD) were assessed and caregivers were interviewed. QoL was measured with the proxy rating Quality of Life in Late Stage Dementia (QUALID) scale. Results: 93 persons with YOD and 98 with LOD were included. No significant differences in QoL were detected. Determinants of QoL were similar in YOD and LOD. Behavioral and psychological symptoms of dementia (BPSD), suffering and other distressing symptoms were associated with a lower QoL. In YOD but not in LOD antipsychotic treatment was associated with low QoL. The group of persons who were younger than 65 years at the time of the study visit experienced significantly more distressing symptoms than older PWAD. Conclusion: Overall, persons with advanced YOD do not appear to be disadvantaged compared to old and oldest PWAD. Special attention, however, must be paid to the group of the very young persons who seem to be particularly vulnerable.

Mingyan Guo, Jun Peng, Xiaoyan Huang, Lingjun Xiao, Fenyan Huang, Zhiyi Zuo
Gut Microbiome Features of Chinese Patients Newly Diagnosed with Alzheimer’s Disease or Mild Cognitive Impairment
Abstract: Background: Patients with Alzheimer’s disease (AD) have gut microbiome alterations compared with healthy controls. However, previous studies often assess AD patients who have been on medications or other interventions for the disease. Also, simultaneous determination of gut microbiome in patients with mild cognitive impairment (MCI) or AD in a study is rare. Objective: To determine whether there was a gut microbiome alteration in patients newly diagnosed with AD or MCI and whether the degree of gut microbiome alteration was more severe in patients with AD than patients with MCI. Methods: Fecal samples of 18 patients with AD, 20 patients with MCI, and 18 age-matched healthy controls were collected in the morning for 16S ribosomal RNA sequencing. No patient had medications or interventions for AD or MCI before the samples were collected. Results: Although there was no difference in the microbial α diversity among the three groups, patients with AD or MCI had increased β diversity compared with healthy controls. Patients with AD had decreased Bacteroides, Lachnospira, and Ruminiclostridium_9 and increased Prevotella at the genus level compared with healthy controls. The changing direction of these genera in patients with MCI was the same as patients with AD. However, Lachnospira was the only genus whose abundance in patients with MCI was statistically significantly lower than healthy controls. Bacteroides, Lachnospira, and Ruminiclostridium_9 were positively associated with better cognitive functions whereas Prevotella was on the contrary when subjects of all three groups were considered. The negative correlation of Prevotella with cognitive functions remained among patients with MCI. Conclusion: Patients newly diagnosed with AD or MCI have gut dysbiosis that includes the decrease of potentially protective microbiome, such as Bacteroides, and the increase of microbiome that can promote inflammation, such as Prevotella. Our results support a novel idea that the degree of gut dysbiosis is worsened with the disease stage from MCI to AD.

Daniel A. Llano, Viswanath Devanarayan, for the Alzheimer’s Disease Neuroimaging Initiative
Serum Phosphatidylethanolamine and Lysophosphatidylethanolamine Levels Differentiate Alzheimer’s Disease from Controls and Predict Progression from Mild Cognitive Impairment
Abstract: Background: There is intense interest in the development of blood-based biomarkers, not only that can differentiate Alzheimer’s disease (AD) from controls, but that can also predict conversion from mild cognitive impairment (MCI) to AD. Serum biomarkers carry the potential advantage over imaging or spinal fluid markers both in terms of cost and invasiveness. Objective: Our objective was to measure the potential for serum lipid markers to differentiate AD from age-matched healthy controls as well as to predict conversion from MCI to AD. Methods: Using a publicly-available dataset, we examined the relationship between baseline serum levels of 349 known lipids from 16 classes of lipids and disease state as well as the prediction of conversion from MCI to AD. Results: We observed that several classes of lipids (cholesteroyl ester, phosphatidylethanolamine, lysophosphatidylethanolamine, and acylcarnitine) differentiated AD from normal controls. Among these, only two classes, phosphatidylethanolamine (PE) and lysophosphatidylethanolamine (lyso-PE), predicted time to conversion from MCI to AD. Low levels of PE and high levels of lyso-PE result in two-fold faster median time to progression from MCI to AD, with hazard ratios 0.62 and 1.34, respectively. Conclusion: These data suggest that serum PE and lyso-PE may be useful biomarkers for predicting MCI to AD conversion. In addition, since PE is converted to lyso-PE by phospholipase A2, an important inflammatory mediator that is dysregulated in AD, these data suggest that the disrupted serum lipid profile here may be related to an abnormal inflammatory response early in the AD pathologic cascade.

Guang-Xiang Yu, Ting Zhang, Xiao-He Hou, Ya-Nan Ou, Hao Hu, Zuo-Teng Wang, Yu Guo, Wei Xu, Lin Tan, Jin-Tai Yu, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative
Associations of Vascular Risk with Cognition, Brain Glucose Metabolism, and Clinical Progression in Cognitively Intact Elders
Abstract: Background: Increasing evidence supports an important role of vascular risk in cognitive decline and dementia. Objective: This study aimed to examine whether vascular risk was associated with cognitive decline, cerebral hypometabolism, and clinical progression in cognitively intact elders. Methods: Vascular risk was assessed by the Framingham Heart Study general Cardiovascular disease (FHS-CVD) risk score. The cross-sectional and longitudinal associations of FHS-CVD risk score with cognition and brain glucose metabolism were explored using multivariate linear regression and linear mixed effects models, respectively. The risk of clinical progression conversion was assessed using Kaplan–Meier survival curves and multivariate Cox proportional hazard models. Results: A total of 491 cognitively intact elders were included from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants with high FHS-CVD risk scores had lower baseline Mini-Mental State Examination (MMSE) (p = 0.009), executive function (EF) (p < 0.001), memory function (MEM) (p < 0.001) scores, and F18-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake (p < 0.001) than those with low FHS-CVD risk scores. In longitudinal analyses, individuals with higher FHS-CVD risk scores had greater longitudinal declines in MMSE (p = 0.043), EF (p = 0.029) scores, and FDG-PET uptake (p = 0.035). Besides, individuals with a higher vascular risk had an increased risk of clinical progression (p = 0.004). Conclusion: These findings indicated effects of vascular risk on cognitive decline, cerebral hypometabolism, and clinical progression. Early detection and management of vascular risk factors might be useful in the prevention of dementia.

Mami Takemoto, Toru Yamashita, Yasuyuki Ohta, Koh Tadokoro, Yoshio Omote, Ryuta Morihara, Koji Abe
Cerebral Microbleeds in Patients with Parkinson’s Disease and Dementia with Lewy Bodies: Comparison Using Magnetic Resonance Imaging and 99mTc-ECD SPECT Subtraction Imaging
Abstract: Background: Cerebral microbleeds (CMBs) in patients with Parkinson’s disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. Objective: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99mTc-ECD SPECT subtraction images of these two diseases. Methods: We examined 112 patients with PD (53 males and 59 females; age: 77.4 ± 3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1 ± 6.7 years) using brain magnetic resonance imaging (MRI) and 99mTc-ECD SPECT subtraction imaging. Results: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7 ± 1.1) than the latter (0.2 ± 0.5, p<0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7–17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. Conclusion: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.

Suhail Ismail Shiekh, Sharon Louise Cadogan, Liang-Yu Lin, Rohini Mathur, Liam Smeeth, Charlotte Warren-Gash (Handling Associate Editor: M. Arfan Ikram)
Ethnic Differences in Dementia Risk: A Systematic Review and Meta-Analysis
Abstract: Background: Globally around 50 million people have dementia. Risk factors for dementia such as hypertension and diabetes are more common in Black, Asian, and other ethnic minorities. There are also marked ethnic inequalities in care seeking, likelihood of diagnosis, and uptake of treatments for dementia. Nevertheless, ethnic differences in dementia incidence and prevalence remain under-explored. Objective: To examine published peer-reviewed observational studies comparing age-specific or age-adjusted incidence or prevalence rates of dementia between at least two ethnic groups. Methods: We searched seven databases on 1 September 2019 using search terms for ethnicity, dementia, and incidence or prevalence. We included population-based studies comparing incidence or prevalence of dementia after accounting for age of at least two ethnic groups in adults aged 18 or more. Meta-analysis was conducted for eligible ethnic comparisons. Results: We included 12 cohort studies and seven cross-sectional studies. Thirteen were from the US, and two studies each from the UK, Singapore, and Xinjiang Uyghur Autonomous Region in China. The pooled risk ratio for dementia incidence obtained from four studies comparing Black and White ethnic groups was 1.33 (95%CI 1.07-1.65; I-squared=58.0%). The pooled risk ratio for dementia incidence comparing the Asian and White ethnic groups was 0.86 (95%CI 0.728-1.01; I-squared=43.9%). There was no difference in the incidence of dementia for Latino ethnic group compared to the White ethnic group. Conclusion: Evidence to date suggest there are ethnic differences in risk of dementia. Better understanding of the drivers of these differences may inform efforts to prevent or treat dementia.

Claire Rühlmann, David Dannehl, Marcus Brodtrück, Andrew C. Adams, Jan Stenzel, Tobias Lindner, Bernd J. Krause, Brigitte Vollmar, Angela Kuhla
Neuroprotective Effects of the FGF21 Analogue LY2405319
Abstract: Background: To date, there are no effective treatments for Alzheimer’s disease (AD). Thus, a significant need for research of therapies remains. Objective: One promising pharmacological target is the hormone fibroblast growth factor 21 (FGF21), which is thought to be neuroprotective. A clinical candidate for medical use could be the FGF21 analogue LY2405319 (LY), which has a specificity and potency comparable to FGF21. Methods: The present study investigated the potential neuroprotective effect of LY via PPARγ/apoE/abca1 pathway which is known to degrade amyloid-β (Aβ) plaques by using primary glial cells and hippocampal organotypic brain slice cultures (OBSCs) from 30- and 50-week-old transgenic APPswe/PS1dE9 (tg) mice. By LY treatment of 52-week-old tg mice with advanced Aβ deposition, we further aimed to elaborate the effect of LY on AD pathology in vivo. Results: LY application to primary glial cells caused an upregulation of pparγ, apoE, and abca1 mRNA expression and significantly decreased number and area of Aβ plaques in OBSCs. LY treatment in tg mice increased cerebral [18F]FDG uptake and N-acetylaspartate/creatine ratio indicating enhanced neuronal activity and integrity. Although LY did not reduce the number of Aβ plaques in tg mice, the number of iba1-positive cells was significantly decreased indicating reduced microgliosis. Conclusion: These data identified LY in vitro as an activator of Aβ degrading genes leading to cerebral Aβ load amelioration in early and late AD pathology. Although Aβ plaque reduction by LY failed in vivo, LY may be used as therapeutic agent to treat AD-related neuroinflammation and impaired neuronal integrity.

Xudong Li, Miaoxin Shen, Yi Jin, Shuhong Jia, Zhi Zhou, Ziling Han, Xiangfei Zhang, Xiaopeng Tong, Jinsong Jiao (Handling Associate Editor: Jin-Tai Yu)
Validity and Reliability of the New Chinese Version of the Frontal Assessment Battery-Phonemic
Abstract: Background: Alzheimer’s disease dementia (ADD) is an important health problem in the world. Objective: The present study investigated the validity and reliability of a new version of the Frontal Assessment Battery (FAB) named the FAB-phonemic (FAB-P). Methods: A total of 76 patients with ADD, 107 patients with amnestic mild cognitive impairment (aMCI), 37 patients with non-amnestic MCI (naMCI), and 123 healthy controls were included in this study. All participants were evaluated with the FAB-P and the cognitive assessments according to a standard procedure. Results: The global FAB-P scores in patients with ADD were lower than those of patients with aMCI, patients with naMCI, and healthy controls (p<0.001). Patients with aMCI performed worse than healthy controls (p<0.001). The interrater reliability, test-retest reliability, and Cronbach's alpha coefficient for the FAB-P were 0.997, 0.819, and 0.736, respectively. The test could distinguish the patients with mild ADD, aMCI, and naMCI from healthy controls with classification accuracy of 89.4%, 70.9%, and 61.6%, respectively. It could also discriminate between the patients with ADD and aMCI, between those with ADD and naMCI, and between those with aMCI and naMCI with classification accuracy of 73.8%, 83.9%, and 58.0%, respectively. The regression analysis revealed that the Montreal Cognitive Assessment and the Stroop Color Word Test Part C had the greatest contribution to FAB-P score variance. Conclusion: The FAB-P is a valid and reliable tool for evaluating frontal lobe function and can effectively discriminate ADD, aMCI, and naMCI.

Enrico Peira, Matteo Grazzini, Mateo Bauckneht, Francesco Sensi, Paolo Bosco, Dario Arnaldi, Silvia Morbelli, Andrea Chincarini, Matteo Pardini, Flavio Nobili (Handling Associate Editor: Benedict Albensi)
Probing the Role of a Regional Quantitative Assessment of Amyloid PET
Abstract: Background: In clinical practice, the amy-PET is globally inspected to provide a binary outcome, but the role of a regional assessment has not been fully investigated yet. Objective: To deepen the role of regional amyloid burden and its implication on clinical-neuropsychological features. Materials: Amy-PET and a complete neuropsychological assessment (Trail Making Test, Rey Auditory Verbal Learning Test, semantic verbal fluency, symbol digit, Stroop, visuoconstruction) were available in 109 patients with clinical suspicion of Alzheimer’s disease. By averaging the standardized uptake value ratio and ELBA, a regional quantification was calculated for each scan. Patients were grouped according to their overall amyloid load: correlation maps, based on regional quantification, were calculated and compared. A regression analysis between neuropsychological assessment and the regional amyloid-β (Aβ) load was carried out. Results: Significant differences were observed between the correlation maps of patients at increasing levels of Aβ and the overall dataset. The Aβ uptake of the subcortical gray matter resulted not related to other brain regions independently of the global Aβ level. A significant association of semantic verbal fluency was observed with ratios of cortical and subcortical distribution of Aβ which represent a coarse measure of differences in regional distribution of Aβ. Conclusion: Our observations confirmed the different susceptibility to Aβ accumulation among brain regions. The association between cognition and Aβ distribution deserves further investigations: it is possibly due to a direct local effect or it represents a proxy marker of a more aggressive disease subtype. Regional Aβ assessment represents an available resource on amy-PET scan with possibly clinical and prognostic implications.

Muthuvel Jayachandran, Virginia M. Miller, Brian D. Lahr, Kent R. Bailey, Val J. Lowe, Julie A. Fields, Michelle M. Mielke, Kejal Kantarci
Peripheral Markers of Neurovascular Unit Integrity and Amyloid-β in the Brains of Menopausal Women
Abstract: Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women. Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n=29), transdermal 17β-estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1-42 (Aβ1-42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs. Results: Only the number of microvesicles positive for Aβ1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p=0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p= 0.045). Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

Mo Li, Rena Li, Ji-hui Lyu, Jian-hua Chen, Wei Wang, Mao-long Gao, Wen-jie Li, Jie De, Han-yan Mu, Wei-gang Pan, Pei-xian Mao, Xin Ma (Handling Associate Editor: Jia Jianping)
Relationship Between Alzheimer’s Disease and Retinal Choroidal Thickness: A Cross-Sectional Study
Abstract: Background: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Objective: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. Methods: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. Results: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81 ± 81.30) µm versus (233.79 ± 38.29) µm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (β = -0.772, p = 0.000) and age (β = -0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR=0.984, 95% CI: 0.972-0.997). Conclusion: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.

Taylor Rigby, David K. Johnson, Angela Taylor, James E. Galvin
Comparison of the Caregiving Experience of Grief, Burden, and Quality of Life in Dementia with Lewy Bodies, Alzheimer’s Disease, and Parkinson’s Disease Dementia
Abstract: Background: Caregivers of persons living with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) are faced with numerous challenges. However, little is known about the caregiving experience across different dementias. Objective: The aims of this cross-sectional study were to examine the differences in the caregiver experience between DLB, PDD, and AD. Methods: Respondents were caregivers (N=515; 384 DLB, 69 AD, 62 PDD) who completed a 230-question survey including sociodemographics, disease severity, neuropsychiatric symptoms, and measures of grief, burden, depression, quality of life, social support, well-being, care confidence, and mastery/self-efficacy. Results: There were no differences in caregiver age, sex, race, or education, or in the distribution of disease severity between diagnostic groups. Constructs were highly intercorrelated with positive attributes (caregiver QoL, care recipient QoL, social support, well-being, mastery and care confidence) being inversely correlated with negative attributes (burden, grief, and depression). Across dementia etiologies, no differences were reported for quality of life, social support, depression, well-being, psychological well-being, mastery, care confidence, burden or grief. Instead, we found that the caregiver’s experience was dependent on caregiver characteristics, person living with dementia characteristics and their most disturbing symptom, with behavior, personality changes, and sleep having the greatest effect on constructs. Conclusion: Caregiver ratings of psychosocial constructs may be more dependent on care recipient-caregiver dyad characteristics and the current symptoms than the underlying cause of those symptoms. Interventions to improve the caregiving experience should be developed to address specific psychosocial constructs rather than focusing on disease etiology or stage.

Giacomo Tondo*, Cecilia Boccalini*, Silvia Paola Caminiti, Luca Presotto, Massimo Filippi, Giuseppe Magnani, Giovanni B. Frisoni, Sandro Iannaccone, Daniela Perani *These authors contributed equally to this work.
Brain Metabolism and Microglia Activation in Mild Cognitive Impairment: A Combined [18F]FDG and [11C]-(R)-PK11195 PET Study
Abstract: Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11C]-(R)-PK11195 and [18F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18F]FDG-PET and [11C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β=-0.804; p=0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes.

Cong Cong, Wanying Zhang, Xiaojing Qian, Wenying Qiu, Chao Ma
Significant Overlap of α-Synuclein, Amyloid-β, and Phospho-Tau Pathologies in Neuropathological Diagnosis of Lewy-Related Pathology
Abstract: Background: Lewy-related pathology (LRP), primarily comprised of α-synuclein, is a typical neuropathological change that has been identified in many neurodegenerative disorders such as Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies. Objective: To investigate the distribution of LRP in the China Human Brain Bank, the co-occurrence of neuropathologic features of Alzheimer’s disease (AD) in LRP cases, and LRP-related cognitive dysfunction. Methods: LRP neuropathological diagnosis was performed in 180 postmortem brains. AD neuropathological diagnosis was then performed in the 21 neuropathologically-diagnosed LRP cases. Antemortem cognitive functioning evaluation (Everyday Cognitive, ECog) was assessed for brain donors by the immediate kin of the donor within 24 hours after death. Results: 12% (21 in 180) postmortem brains were neuropathologically diagnosed as LRP cases. 86% (18 in 21) aged above 80, 81% (17 in 21) LRP cases combined with AD neuropathology, and 62% (13 in 21) combined with both the intermediate or high-level amyloid-β and phospho-tau pathologies. ECog scores showed significant differences between the groups of LRP brainstem-predominant type and LRP diffuse neocortical type, and between groups of AD and the combined LRP (diffuse neocortical type)-AD. Conclusion: The overlap of neocortical α-synuclein, amyloid-β, phospho-tau, and neuritic plaques in LRP suggested the potential interplay among the common characteristics of proteinopathies in the late stage of neuropathological development of LRP in human brains. The anatomic progression of LRP, the process of α-synuclein spreading from the brainstem to limbic and neocortical regions, might aggravate the deterioration of cognitive function in addition to that effect of AD.

Zahinoor Ismail, Alexander McGirr, Sascha Gill, Sophie Hu, Nils D. Forkert, Eric E. Smith (Handling Associate Editor: Carlo Abbate)
Mild Behavioral Impairment and Subjective Cognitive Decline Predict Cognitive and Functional Decline
Abstract: Background: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease). Objective: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline. Methods: Cognitively normal participants were followed up annually at Alzheimer’s Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome. Results: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR>0, including 23.1% of the MBI+ group, 23.5% of the SCD+ group, and 30.9% of the intersection group of both MBI+ and SCD+ participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42-5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57-6.34] for MBI+SCD- (20.7%), and 8.15 [5.71-11.64] for MBI+SCD+ (30.9%). Conclusion: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment.