Volume 74, Number 2, IN PRESS

Review
Kelly Ceyzériat, Benjamin B. Tournier, Philippe Millet, Giovanni B. Frisoni, Valentina Garibotto, Thomas Zilli
Low-Dose Radiation Therapy: A New Treatment Strategy for Alzheimer’s Disease?
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by extracellular amyloid-β (Aβ) peptide aggregates, forming amyloid plaques, and intracellular deposits of phosphorylated tau. Neuroinflammation is now considered as the third hallmark of AD. The majority of clinical trials tested pharmacological strategies targeting amyloid, tau, and neuroinflammation, with disappointing results overall. In parallel, innovative strategies exploring other pathways and approaches are being tested. In this article, we focus on the rationale and preliminary preclinical evidence for a novel application to AD of a widely used therapeutic strategy for oncological and benign conditions: low-dose radiation therapy (LD-RT). LD-RT has shown to be effective against systemic amyloid deposits, as well as against chronic inflammatory diseases, and could thus be able to modulate amyloid load and neuroinflammation in AD. The anti-amyloid effect could be possibly mediated by the LD-RT action on the β-sheet structure of amyloid fibrils, by breaking H-bonds, and depolymerize glucoaminoglycans which are highly radiation-sensitive molecules associated with amyloid fibrils. The anti-inflammatory effect could be linked to the decrease of leukocytes-endothelial cells interactions and to the stimulation of the release of anti-inflammatory molecules. One preclinical study has observed a dramatic reduction of amyloid plaques 4 weeks post-RT, more important with fractionated protocols at low doses than hypofractionated single dose treatments, associated with modulation of inflammatory and anti-inflammatory cytokines and cognitive improvement. Ongoing Phase I clinical trials will test the ability of LD-RT to hold these promises.

Short Communication
Hope Tobey, Tyler Lucas, Soumen Paul, Stuart S. Berr, Brittney Mehrkens, Per Gunnar Brolinson, Bradley G. Klein, Blaise M. Costa
Mechanoceutics Alters Alzheimer’s Disease Phenotypes in Transgenic Rats: A Pilot Study
Abstract: Current advancements in neurovascular biology relates a mechanoceutics treatment, known as cranial osteopathic manipulation (COM), with Alzheimer’s disease (AD). COM could be used as an evidence-based treatment strategy to improve the symptoms of AD if molecular mechanisms, which currently remain unclear, are elucidated. In the present pilot study, using transgenic rats, we have identified COM mediated changes in behavioral and biochemical parameters associated with AD phenotypes. We expect these changes may have functional implications and that might account for improved clinical outcomes of COM treatment. Further investigations on COM will be helpful to establish an adjunct treatment for AD.

Short Communication
Tim Fleiner, Hannah Dauth, Wiebren Zijlstra, Peter Haussermann
A Structured Physical Exercise Program Reduces Professional Caregiver’s Burden Caused by Neuropsychiatric Symptoms in Acute Dementia Care: Randomized Controlled Trial Results
Abstract: Physical exercise is an effective treatment approach for neuropsychiatric symptoms (NPS), but it is unknown whether the reduction of NPS has an impact on professional caregiver burden. A randomized controlled trial in acute dementia care with N=70 patients, n=35 per group, was conducted. The intervention group (IG) received an exercise program, the control group a social stimulation program. The RM-ANOVA showed a significant group x time interaction with time effects for the IG and decreased caregiver burden due to the exercise program at follow-up. Physical exercise programs may not only be beneficial for the patients but also for their professional caregivers.

Short Communication
Iris L. Uijen*, Justine A. Aaronson*,Esther G.A. Karssemeijer, Marcel G.M. Olde Rikkert, Roy P.C. Kessels (Handling Associate Editor: Olivia Küster) *These authors contributed equally to this work.
Individual Differences in the Effects of Physical Activity on Cognitive Function in People with Mild to Moderate Dementia
Abstract: The aim of this study was to investigate whether the effect of physical activity on cognitive function in persons with dementia is moderated by patient characteristics as Apolipoprotein E and dementia type. We included 101 individuals with dementia and calculated the reliable change index to determine the change in global cognition, executive function, episodic memory, working memory, and processing speed before and after a 12-week exercise training. We found a higher treatment-related benefit in episodic memory in persons with non-Alzheimer’s disease compared to persons with Alzheimer’s disease, and in executive function in individuals with better baseline cognitive function.

Prashant Bharadwaj, Ralph N. Martins
PRKAG2 Gene Expression Is Elevated and its Protein Levels Are Associated with Increased Amyloid-β Accumulation in the Alzheimer’s Disease Brain
Abstract: Increased amyloid-β (Aβ) accumulation associated with abnormal autophagy-lysosomal activity and nutrient kinase dysregulation are common features in Alzheimer’s disease (AD) brain. Recent studies have identified PRKAG2 and TIPRL genes that control nutrient kinase regulated autophagy, and here we determined if their expression is altered in postmortem AD brains. Gene and protein expression of TIPRL were unchanged. However, gene expression of PRKAG2 was increased 3-fold and its protein levels positively correlated with Aβ accumulation in the AD brain. In summary, our findings suggest that increased PRKAG2 is an important contributing factor to Aβ accumulation in the AD brain.

Anika Rädke, Bernhard Michalowsky, Jochen René Thyrian, Tilly Eichler, Feng Xie, Wolfgang Hoffmann (Handling Associate Editor: Anders Wimo)
Who Benefits Most from Collaborative Dementia Care from a Patient and Payer Perspective? A Subgroup Cost-Effectiveness Analysis
Abstract: Background: Dementia care management (DCM) aims to provide optimal treatment for people with dementia (PwD). Treatment and care needs are dependent on patients’ sociodemographic and clinical characteristics and thus, economic outcomes could depend on such characteristics. Objective: To detect important subgroups that benefit most from DCM and for which a significant effect on cost, QALY, and the individual cost-effectiveness could be achieved. Methods: The analysis was based on 444 participants of the DelpHi-trial. For each subgroup, the probability of DCM being cost-effective was calculated and visualized using cost-effectiveness acceptability curves. The impact of DCM on individual costs and QALYs was assessed by using multivariate regression models with interaction terms. Results: The probability of DCM being cost-effective at a willingness-to-pay of 40,000€/QALY was higher in females (96% versus 16% for males), in those living alone (96% versus 26% for those living not alone), in those being moderately to severely cognitively (100% versus 3% for patients without cognitive impairment) and functionally impaired (97% versus 16% for patients without functional impairment), and in PwD having a high comorbidity (96% versus 26% for patients with a low comorbidity). Multivariate analyses revealed that females (b=-10,873; SE=4,775, p=0.023) who received the intervention had significantly lower healthcare cost. DCM significantly improved QALY for PwD with mild and moderate cognitive (b=+0.232, SE=0.105) and functional deficits (b=+0.200, SE=0.095). Conclusion: Patients characteristics significantly affect the cost-effectiveness. Females, patients living alone, and those being moderately cognitively and functionally impaired benefit most from DCM. For those subgroups, healthcare payers could gain the highest cost savings and the highest effects on QALYs when DCM will be implemented.

Rianne A.A. de Heus, Stacha F.I. Reumers, Alba van der Have, Maxime Tumelaire, Phillip J. Tully, Jurgen A.H.R. Claassen (Handling Associate Editor: Ronan O'Caoimh)
Day-to-Day Home Blood Pressure Variability Is Associated with Cerebral Small Vessel Disease Burden in a Memory Clinic Population
Abstract: Background: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-to-day BPV also relates to cSVD has not been investigated. Objective: To investigate the cross-sectional association between day-to-day BPV and total cSVD MRI burden in older memory clinic patients. Methods: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0-4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP. Results: For 82 patients (aged 71.2±7.9 years), mean home BP was 140/79±15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV=1.29, 95% confidence interval=1.04-1.60, p=0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden. Conclusion: Day-to-day systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints.

Na-Yeon Jung*, Eun Soo Kim*, Hyang-Sook Kim, Sumin Jeon, Myung Jun Lee, Kyoungjune Pak, Jae-Hyeok Lee, Young Min Lee, Kangyoon Lee, Jin-Hong Shin, Jun Kyeung Ko, Jae Meen Lee, Jin A Yoon, Chungsu Hwang, Kyung-Un Choi, Eun Chong Lee, Joon-Kyung Seong, Gi Yeong Huh, Dae-Seong Kim, Eun-Joo Kim (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Comparison of Diagnostic Performances Between Cerebrospinal Fluid Biomarkers and Amyloid PET in a Clinical Setting
Abstract: The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aβ1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer’s disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ1-42, t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ1-42 and t-tau/Aβ1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ1-42. However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ1-42 and amyloid PET, baseline CSF Aβ1-42 better predicted AD conversion.

Yue Hong, Rachel L. Alvarado, Amod Jog, Douglas N. Greve, David H. Salat (Handling Associate Editor: Andrea Zammit)
Serial Reaction Time Task Performance in Older Adults with Neuropsychologically Defined Mild Cognitive Impairment
Abstract: Background: Studies have found that individuals with mild cognitive impairment (MCI) exhibit a range of deficits outside the realm of primary explicit memory, yet the role of response speed and implicit learning in older adults with MCI have not been established. Objective: The current study aims to explore and document response speed and implicit learning in older adults with neuropsychologically defined MCI using a simple serial reaction (SRT) task. In addition, the study aims to explore the feasibility of a novel utilization of the simple cognitive task using machine learning procedures as a proof of concept. Method: Participants were 22 cognitively healthy older adults and 20 older adults with MCI confirmed through comprehensive neuropsychological evaluation. Two-sample t-test, multivariate regression, and mixed-effect models were used to investigate group difference in response speed and implicit learning on the SRT task. We also explored the potential utility of SRT feature analysis through random forest classification. Results: With demographic variables controlled, the MCI group showed overall slower reaction time and higher error rate compared to the cognitively healthy volunteers. Both groups showed significant simple motor learning and implicit learning. The learning patterns were not statistically different between the two groups. Random forest classification achieved overall accuracy of 80.9%. Conclusions: Individuals with MCI demonstrated slower reaction time and higher error rate compared to cognitively healthy volunteers but demonstrated largely preserved motor learning and implicit sequence learning. Preliminary results from random forest classification using features from SRT performance supported further research in this area.

Claudio Liguori, Matteo Spanetta, Francesca Izzi, Flaminia Franchini, Marzia Nuccetelli, Giulia Maria Sancesario, Simona Di Santo, Sergio Bernardini, Nicola Biagio Mercuri, Fabio Placidi (Handling Associate Editor: Luigi Ferini-Strambi)
Sleep-Wake Cycle in Alzheimer’s Disease Is Associated with Tau Pathology and Orexin Dysregulation
Abstract: Background: Alzheimer's disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. Objective: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. Methods: Mild to moderate AD patients were enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. Results: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. Conclusion: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients.

Manja Koch, Simona Costanzo, Annette L. Fitzpatrick, Oscar L. Lopez, Steven DeKosky, Lewis H. Kuller, Julie Price, Rachel H. Mackey, Majken K. Jensen, Kenneth J. Mukamal
Alcohol Consumption, Brain Amyloid-β Deposition, and Brain Structural Integrity Among Older Adults Free of Dementia
Abstract: Background: Light to moderate alcohol consumption has been variably associated with lower or higher risk of dementia, but effects on Alzheimer’s disease pathology are less clear. Objective: We determined whether late-life alcohol consumption was associated with Alzheimer’s disease pathology among older adults. Methods: We assessed the associations of alcohol consumption self-reported in 2000-2002 with brain amyloid-β deposition on PET scans, and white matter lesion and hippocampal volume on MRIs measured 7-9 years later in 189 participants of the Ginkgo Evaluation of Memory Study (age 75-87 years at baseline) who were free of clinical dementia, using multivariable-adjusted and inverse probability-weighted robust linear regression models. Results: Alcohol consumption was not statistically significantly associated with amyloid-β deposition (standardized uptake value ratio difference per drink: -0.013 [95%CI: -0.027, 0.002]). Both non-drinkers and participants consuming ≥1 drink(s)/week had higher white matter lesion volume (% intracranial volume) than did the reference group of those consuming <1 drink/week (differences: 0.25 % [95%CI: 0.01, 0.50]; 0.26 % [95%CI: 0.02, 0.50]). The association of alcohol consumption and hippocampal volume was modified by age (p = 0.02). Among participants younger than 77 years, participants consuming 1-7 drinks/week had larger hippocampal volume compared with participants consuming <1 drink/week. Conclusions: Alcohol consumption was not statistically significantly associated with amyloid-β deposition 7-9 years later. Non-drinking and greater alcohol consumption were associated with higher white matter lesion volume compared with drinking <1 drink/week. Moderate drinking was associated with higher hippocampal volume in younger individuals. Given the selective nature of this population and adverse health effects of excessive alcohol consumption, these findings warrant further investigation, but cannot be translated into clinical recommendations.

Ting-ting Hou, Yun-Dan Han, Lin Cong, Cui-cui Liu , Xiao-Yan Liang, Fu-zhong Xue, Yi-feng Du (Handling Associate Editor: Jin-Tai Yu)
Apolipoprotein E Facilitates Amyloid-β Oligomer-Induced Tau Phosphorylation
Abstract: Hyperphosphorylated tau is one of the key characteristics of Alzheimer’s disease (AD), and tau pathology correlates with cognitive impairment in AD better than amyloid-β (Aβ) pathology. Thus, a complete understanding of the relevant factors involved in tau phosphorylation is important for AD treatment. APOE ε4, the strongest genetic risk factor for AD, was found to be involved in tau pathology in frontotemporal dementia. This result indicated that apolipoprotein E (ApoE) may also participate in tau phosphorylation in AD. In the present study, we injected Aβ oligomer (AβO) into the lateral ventricles of wild-type (WT) mice and apoE-/- mice to test the process of tau phosphorylation in the acute phase. We found that the phosphorylated tau and phosphokinase levels were higher in WT mice than in apoE-/- mice. These phenomena were also confirmed in vitro. ApoE ε4-treated apoE-/- neurons exhibited more phosphorylated tau than ApoE ε2- and ApoE ε3-treated neurons. We also found that AβO induced more serious inflammation in WT mice and in ApoE-positive cultured neurons. Anti-inflammatory treatment reduced the phosphorylated tau level induced by AβOs in ApoE-positive neurons. These results suggest that ApoE may facilitate the phosphorylation of tau induced by AβO via inflammation.

Lin Sun*, Baoying Cheng*, Yuxun Zhou*, Yating Fan, Wei Li, Qi Qiu, Yuan Fang, Shifu Xiao, Honghua Zheng, Xia Li *These authors contributed equally to this work.
ErbB4 Mutation that Decreased NRG1-ErbB4 Signaling Involved in the Pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
Abstract: Background: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders. Objective: To identify the relationship of ErbB4 mutation and ALS/FTD. Methods: Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation. Results: A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD. Conclusion: We firstly found ErbB4 mutation to be identified in ALS/FTD.

Hamel Patel, Raquel Iniesta, Daniel Stahl, Richard J.B. Dobson*, Stephen J. Newhouse* *These authors are joint last authors.
Working Towards a Blood-Derived Gene Expression Biomarker Specific for Alzheimer’s Disease
Abstract: Background: The typical approach to identify blood-derived gene expression signatures as a biomarker for Alzheimer’s disease (AD) have relied on training classification models using AD and healthy controls only. This may inadvertently result in the identification of markers for general illness rather than being disease-specific. Objective: Investigate whether incorporating additional related disorders in the classification model development process can lead to the discovery of an AD-specific gene expression signature. Methods: Two types of XGBoost classification models were developed. The first used 160 AD and 127 healthy controls and the second used the same 160 AD with 6,318 upsampled mixed controls consisting of Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, bipolar disorder, schizophrenia, coronary artery disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and cognitively healthy subjects. Both classification models were evaluated in an independent cohort consisting of 127 AD and 687 mixed controls. Results: The AD versus healthy control models resulted in an average 48.7% sensitivity (95% CI=34.7-64.6), 41.9% specificity (95% CI=26.8-54.3), 13.6% PPV (95% CI=9.9-18.5), and 81.1% NPV (95% CI=73.3-87.7). In contrast, the mixed control models resulted in an average of 40.8% sensitivity (95% CI=27.5-52.0), 95.3% specificity (95% CI=93.3-97.1), 61.4% PPV (95% CI=53.8-69.6), and 89.7% NPV (95% CI=87.8-91.4). Conclusions: This early work demonstrates the value of incorporating additional related disorders into the classification model developmental process, which can result in models with improved ability to distinguish AD from a heterogeneous aging population. However, further improvement to the sensitivity of the test is still required.

Eleonora Cipollari, Hannah J. Szapary, Antonino Picataggi, Jeffrey T. Billheimer, Catherine A. Lyssenko, Gui-Shuang Ying, Leslie M. Shaw, Mitchel A. Kling, Rima Kaddurah-Daouk, Daniel J. Rader, Domenico Praticò, Nicholas N. Lyssenko, for the Alzheimer’s Disease Metabolomics Consortium (Handling Associate Editor: Patricia Mecocci)
Correlates and Predictors of Cerebrospinal Fluid Cholesterol Efflux Capacity from Neural Cells, a Family of Biomarkers for Cholesterol Epidemiology in Alzheimer’s Disease
Abstract: Background: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer’s disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD. Objective: To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects. Methods: We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis. To measure cerebrospinal fluid (CSF) CECs from neurons, microglia, and astrocytes, CSF was exposed to, correspondingly, neuronal, microglial, and astrocytic cholesterol source cells. Human neuroblastoma SH-SY5Y, mouse microglial N9, and human astroglial A172 cells were used as the cholesterol source cells. CSF samples were screened for contamination with blood. CSF CECs were measured in a small cohort of 22 individuals. Results: CSF CECs from neurons, microglia, and astrocytes were moderately to moderately strongly correlated with CSF concentrations of cholesterol, apolipoprotein A-I, apolipoprotein E, and clusterin (Pearson’s r = 0.53-0.86), were in poor agreement with one another regarding CEC of the CSF samples (Lin’s concordance coefficient rc = 0.71-0.76), and were best predicted by models consisting of, correspondingly, CSF phospholipid (R2 = 0.87, p < 0.0001), CSF apolipoprotein A-I and clusterin (R2 = 0.90, p < 0.0001), and CSF clusterin (R2 = 0.62, p = 0.0005). Conclusion: Characteristics of the CSF CEC metrics suggest a potential for independent association with AD and provision of fresh insight into the role of cholesterol in AD pathogenesis.

Wei Zhang, Peng Luo (Handling Associate Editor: Yong Guo)
Myocardial Infarction Predisposes Neurodegenerative Diseases
Abstract: Cardiovascular disorders, e.g., atherosclerosis and hypertension, increase susceptibility to neurodegenerative diseases, like dementia and Alzheimer’s disease (AD), with undetermined mechanisms. Moreover, whether myocardial infarction (MI) may similarly increases occurrence of AD is unknown. In the current study, we performed a MI model in wild-type and AD-prone APP/PS1 mice and assessed the development of AD in these mice. We found that MI-treated mice of both wild-type and APP/PS1 behaved poorer in a social recognition test, the Morris water maze, and the plus-maze discriminative avoidance task, compared to sham-treated controls. Mechanistically, MI significantly increased the levels of reactive oxygen species, as well as increased deposition of amyloid-β peptide aggregates and phosphorylation of tau protein in mouse brain, two signature pathological features for AD. Moreover, the microglia in the MI-mice appeared to alter polarization to a more proinflammatory phenotype. Together, our data suggest that MI may be a predisposing factor for AD development.

Maureen Okafor, Jonathon A. Nye, Mahsa Shokouhi, Leslie Shaw, Felicia Goldstein, Ihab Hajjar (Handling Associate Editor: Alden Gross)
18F-Flortaucipir PET Associations with Cerebrospinal Fluid, Cognition, and Neuroimaging in Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer's disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). Objective: To determine associations between 18F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. Methods: In 29 participants 50 years or older with MCI-AD, 18F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau181p (P-tau), amyloid-β (Aβ), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11C-Pittsburgh compound B PET was simultaneously conducted in 20 participants. Associations between 18F-flortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). Results: Whole brain 18F-flortaucipir SUVr was significantly associated with CSF T-tau (r=0.68, p<0.001) and P-tau (r=0.42, p=0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (T-tau: r=0.69, p<0.001; P-tau: r=0.49, p=0.02). Voxel-wise analysis confirmed these regional associations. 18F-flortaucipir PET was also associated with CSF Aβ (r=-0.45, p=0.03), episodic memory (r=-0.61, p=0.001), visuospatial working memory (r=-0.46, p=0.02), and brain cortical thickness (r=-0.44, p=0.03) but not hippocampal volume. In the amyloid PET subset, although 11C-PiB PET associated strongly with 18F-flortaucipir (r=0.79, p≤0.001), associations were stronger between 11C-PiB and key outcomes, compared to 18F-flortaucipir. Conclusion: 18F-flortaucipir PET is moderately associated with CSF AD biomarkers and other AD-related phenotypes. The associations in this MCI-AD sample are stronger than previously described in other populations.

Wenqing Xia*, Yong Luo*, Yu-Chen Chen, Huiyou Chen, Jianhua Ma, Xindao Yin (Handling Associate Editor: Shaohua Wang) *These authors contributed equally to this work.
Glucose Fluctuations Are Linked to Disrupted Brain Functional Architecture and Cognitive Impairment
Abstract: Background: Type 2 diabetes mellitus (T2DM) accelerates cognitive decline, which is believed to be triggered by aberrant neural activity. Objective: To explore how glucose fluctuations impact brain functional architecture and cognition in T2DM patients. Methods: T2DM patients were divided according to glycemic variability, forming two categories: patients with fluctuating glucose levels and patients with stable glucose levels. Degree centrality (DC) was calculated within the cerebral gray matter of each participant and was compared among the two patient groups and a healthy control group. The relationships between glucose fluctuations and aberrant DC and cognitive performance, as well as the relationship between aberrant DC and cognitive performance, were further explored. Results: Compared with T2DM patients with stable glucose levels, T2DM patients with fluctuating glucose levels exhibited significantly worse performance on the Montreal Cognitive Assessment, Trail Making Test-B (TMT-B), and verbal fluency test (VFT), as well as significant decreases in DC in certain regions, most of which were within the default mode network. In the combined T2DM group, the mean amplitude of glycemic excursions (MAGE) was positively correlated with TMT-B scores and negatively correlated with VFT scores. Moreover, the MAGE was negatively correlated with DC in the left medial prefrontal cortex (mPFC). In addition, TMT-B scores were negatively correlated with reduced DC in the left mPFC. Conclusion: These findings further contribute to the mounting evidence of the effects of glycemic variability on the diabetic brain. Tightened control of glucose fluctuations might prevent cognitive decline and changes in brain functional architecture in T2DM individuals.

Sofia Toniolo, Laura Serra, Giusy Olivito, Carlo Caltagirone, Nicola B. Mercuri, Camillo Marra, Mara Cercignani, Marco Bozzali
Cerebellar White Matter Disruption in Alzheimer’s Disease Patients: A Diffusion Tensor Imaging Study
Abstract: The cognitive role of the cerebellum has recently gained much attention, and its pivotal role in Alzheimer’s disease (AD) has now been widely recognized. Diffusion tensor imaging (DTI) has been used to evaluate the disruption of the microstructural milieu in AD, and though several white matter (WM) tracts such as corpus callosum, inferior and superior longitudinal fasciculus, cingulum, fornix, and uncinate fasciculus have been evaluated in AD, data on cerebellar WM tracts are currently lacking. We performed a tractography-based DTI reconstruction of the middle cerebellar peduncle (MCP), and the left and right superior cerebellar peduncles separately (SCPL and SCPR) and addressed the differences in fractional anisotropy (FA), axial diffusivity (Dax), radial diffusivity (RD), and mean diffusivity (MD) in the three tracts between 50 patients with AD and 25 healthy subjects. We found that AD patients showed a lower FA and a higher RD compared to healthy subjects in MCP, SCPL, and SCPR. Moreover, a higher MD was found in SCPR and SCPL and a higher Dax in SCPL. This result is important as it challenges the traditional view that WM bundles in the cerebellum are unaffected in AD and might identify new targets for therapeutic interventions.

Hailey J. James, Courtney Harold Van Houtven, Steven Lippmann, James R. Burke, Megan Shepherd-Banigan, Emmanuelle Belanger, Terrie Fox Wetle, Brenda L. Plassman (Handling Associate Editor: Joshua Grill)
How Accurately Do Patients and Their Care Partners Report Results of Amyloid-β PET Scans for Alzheimer’s Disease Assessment?
Abstract: Background: Amyloid-β PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer’s disease if Medicare approves reimbursement for the scans. However, little is known about patients’ and their care partners’ interpretation of scan results. Objective: This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-β PET scans and factors related to correct reporting. Methods: A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from a sub-sample of 200 dyads. Results: Eighty-three percent of patients and 85% of care partners correctly reported amyloid-β PET scan results. Patients’ higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: -0.004, 95% CI: -0.007, -0.000), but also care partners accurately reporting scan results (ME: -0.006, 95% CI: -0.007, -0.001), as well as decreased concordance between patient and care partner reports (ME: -0.004, 95% CI: -0.007, -0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. Conclusion: Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-β PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information.

Laetitia Miguel, Thierry Frebourg, Dominique Campion, Magalie Lecourtois
Moderate Overexpression of Tau in Drosophila Exacerbates Amyloid-β-Induced Neuronal Phenotypes and Correlates with Tau Oligomerization
Abstract: Alzheimer’s disease (AD) is neuropathologically defined by two key hallmarks: extracellular senile plaques composed primarily of amyloid-β (Aβ) peptide and intraneuronal neurofibrillary tangles, containing abnormally hyperphosphorylated tau protein. The tau protein is encoded by the MAPT gene. Recently, the H1 and H2 haplotypes of the MAPT gene were associated with AD risk. The minor MAPT H2 haplotype has been linked with a decreased risk of developing late-onset AD (LOAD). MAPT haplotypes show different levels of MAPT/Tau expression with H1 being ~1.5-fold more expressed than H2, suggesting that MAPT expression level could be related to LOAD risk. In this study, we investigated whether this moderate difference in MAPT/Tau expression could influence Aβ-induced toxicity in vivo. We show that modest overexpression of tau protein in Drosophila exacerbates neuronal phenotypes in AβPP/BACE1 flies. The exacerbation of neuronal defects correlates with the accumulation of insoluble dTau oligomers, suggesting that the moderate difference in level of tau expression observed between H1 and H2 haplotypes could influence Aβ toxicity through the production of oligomeric tau insoluble species.

Abigail Livny, Michal Schnaider Beeri, Anthony Heymann, Erin Moshier, Yuval Berman, Mary Mamistalov, Danit-Rivka Shahar, Galia Tsarfaty, Derek Leroith, Rachel Preiss, Laili Soleimani, Jeremy M. Silverman, Barbara B. Bendlin, Andrew Levy, Ramit Ravona-Springer
Vitamin E Intake Is Associated with Lower Brain Volume in Haptoglobin 1-1 Elderly with Type 2 Diabetes
Abstract: Background: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n=24, Hp 2-1: n=77, Hp 2-2: n=80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results: Average age was 70.8 (SD=4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD=1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus' volume; p=0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p=0.0348), increased by 0.429% for Hp 2-1 (p=0.0457), and by 0.077% for Hp 2-2 (p=0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p=0.6011) and superior (p=0.2025) frontal gyri or for the middle temporal gyrus (p=0.503). Conclusions: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype.

Kasra Moazzami, Matthew T. Wittbrodt, Bruno B. Lima, Jeong Hwan Kim, Muhammad Hammadah, Yi-An Ko, Malik Obideen, Naser Abdelhadi, Belal Kaseer, M. Mazen Gafeer, Jonathon A. Nye, Amit J. Shah, Laura Ward, Paolo Raggi, Edmund K. Waller, J. Douglas Bremner, Arshed A. Quyyumi*, Viola Vaccarino* *These authors contributed equally to this work.
Circulating Progenitor Cells and Cognitive Impairment in Men and Women with Coronary Artery Disease
Abstract: Background: Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). Objective: To assess the association between CPCs and memory performance among individuals with CAD. Methods: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45med/CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations enriched for hematopoietic and endothelial progenitors. Results: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all <0.05). There was a significant interaction in the magnitude of this association with race (p<0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. Conclusion: Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study.

Radia Zeghari, Valeria Manera, Roxane Fabre, Rachid Guerchouche, Alexandra König, Minh Khue Phan Tran, Philippe Robert
The “Interest Game”: A Ludic Application to Improve Apathy Assessment in Patients with Neurocognitive Disorders
Abstract: Background: Apathy, a highly prevalent behavioral disorder in Alzheimer's disease and other related disorders, is currently assessed using clinical scales as it is for all neuropsychiatric disorders. Objective: The aim of this study is to propose a new type of assessment using new technologies designed to assess loss of interest by a more implicit and indirect method. Methods: The Interest Game is a form of interactive self-report, where categories of interests are presented in order to quantify them and identify the activities that constitute them. Two indices can be extracted, the number of categories and the number of activities selected. We compared the scores between three groups: Apathetic (A) and Non-Apathetic (NA) subjects (according to the Apathy Diagnostic Criteria) and controls with no objective cognitive impairment. Results: 95 subjects were included. Results showed that subjects from the A group had significantly less interests (both categories and images selected) than the NA group. As expected, the control group selected a higher number of categories than the other groups. The diagnosis (minor or major neurocognitive disorder) and level of education had also a significant effect on the number of categories selected. Furthermore, subjects with major neurocognitive disorder (NCD) had significantly less interests than minor NCD group. The number of categories measure was more sensitive than the number of images selected. Conclusion: The Interest Game is a promising tool to quantify and identify subject interests and differentiate between apathetic and non-apathetic subjects. Future studies should focus on including more apathetic subjects in the minor NCD group and validating this tool with the general population.

Yi Zhu*, Qian Zhong*, Jie Ji*, Jinhui Ma, Han Wu, Yaxin Gao, Nawab Ali, Tong Wang *These authors contributed equally to this work.
Effects of Aerobic Dance on Cognition in Older Adults with Mild Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: Regular aerobic exercises could improve global cognition in older adults with mild cognitive impairment (MCI), such as aerobic dance a type of commonly practiced aerobic exercises. However, its effects remain debatable in improving the cognitive function in patients with MCI. Objective: The aim of this systematic review and meta-analysis is to evaluate the effects of aerobic dance on cognitive function among older adults with MCI. Methods: We searched articles in the MEDLINE, PubMed, Embase, and The Cochrane Library databases from inception to 28 February 2019, with the following criteria: 1) randomized controlled trials; 2) older adults with MCI; 3) aerobic dance intervention. Results: Five studies of 842 participants were identified. This meta-analysis showed that aerobic dance can significantly improve global cognition (Mini-Mental State Examination: MD=1.43; 95%CI:[0.59, 2.27]; p = 0.0009; Alzheimer’s Disease Assessment Scale-Cognitive Subscale: MD= -2.30; 95%CI:[-3.60, -1.00]; p = 0.0005), and delayed recall ability (SMD=0.46 ;95%CI: [0.30, 0.62]; p < 0.00001) in older adults with MCI. In addition, have positive effects on improving executive function (Trial-Making Test A: MD= -2.37 ;95%CI:[-4.16, -0.58]; p = 0.010; Trial-Making Test B: MD = -16.0; 95%CI: [-30.03, -2.11]; p = 0.020) and immediate recall ability (SMD=0.24;95%CI: [0.01, 0.46]; p = 0.04). Conclusion: Aerobic dance significantly improves global cognitive function and memory in older adults with MCI. In addition, it also benefits executive function. However, due to the limitations as the review states, more randomized controlled trials with better study design and larger sample sizes should be conducted in the future research to make it much clearer.

Carlijn M. Maasakkers, Rianne A.A. de Heus, Dick H.J. Thijssen, René J.F. Melis, Paul A. Gardiner, Jurgen A.H.R. Claassen
Objectively-Measured Activity Patterns Are Associated with Home Blood Pressure in Memory Clinic Patients
Abstract: Background: Physicians are cautious to prescribe antihypertensive drugs in frail older adults because of the potential adverse effects, especially in those with cognitive complaints. Lifestyle aspects might provide safe targets to lower blood pressure in older adults. Objective: Our goal was to evaluate the associations between activity patterns and blood pressure in memory clinic patients. Methods: We used an observational cross-sectional study to measure activity patterns with the ActivPAL accelerometer, and simultaneous home blood pressure levels in memory clinic patients (age range 51–87 years old). Office blood pressure was assessed during routine clinical practice. Results: 41 patients (mean age of 74.3 (7.7) years of age, 46% female) were included. Sedentary parameters were associated with higher mean home blood pressure, with the strongest correlation between more prolonged sitting bouts and higher SBP (r=0.58, p<.0001). Physical activity parameters were negatively associated with mean home blood pressure. Adjusted regression estimates remained significant, showing, e.g., a 4.5 (95% CI=1.6;7.4) mmHg increase in SBP for every hour of sitting per day and a -1.0 (95% CI=-1.8;-0.2) mmHg decrease in DBP for every additional 1000 steps per day. No strong correlations were found between any of the activity pattern variables and office blood pressure. Conclusion: Associations between activity pattern variables and blood pressure were only found with home blood pressure measurements, not with office measurements. Longitudinal evaluations of these associations are now needed to explore if reducing prolonged sedentary bouts and increasing step count indeed serve as safe targets to lower blood pressure.

Raquel C. Gardner, Ernesto Rivera, Megan O’Grady, Colin Doherty, Kristine Yaffe, John Corrigan, Jennifer Bogner, Joel Kramer, Fiona Wilson (Handling Associate Editor: Rudy Castellani)
Screening for Lifetime History of Traumatic Brain Injury Among Older American and Irish Adults at Risk for Dementia: Development and Validation of a Web-Based Survey
Abstract: Background: Traumatic brain injury (TBI) is an established risk factor for dementia but mechanisms are uncertain. Accurate TBI exposure classification is critical for cognitive aging research studies seeking to discover mechanisms and treatments of post-TBI dementia. Brief TBI screens, commonly used in epidemiological studies of cognitive aging, are insensitive, leading to exposure mis-classification. Comprehensive TBI interviews, while more sensitive, may be impractical. Objective: We aimed to develop and validate a scalable, self-administered, comprehensive, web-based, TBI exposure survey for use in international cognitive aging research. Methods: We adapted a gold-standard comprehensive TBI interview (the Ohio State University TBI Identification Method; OSU TBI-ID) into a self-administered web-based survey for older adults (Older Adult modification of the OSU TBI-ID; OA OSU TBI-ID). We assessed reliability of our web-based survey versus the gold-standard interview among 97 older adults with normal cognition and mild cognitive impairment (MCI). In addition, we assessed sensitivity of the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) brief TBI screen versus the interview among 70 older adults with normal cognition. Results: Our OA OSU TBI-ID web-based survey had good to excellent reliability versus the interview (κ 0.66-0.73; ICCs 0.68-0.81) even among the sub-set with MCI (κ 0.74-0.88; ICCs 0.76-0.85), except for several age-at-injury variables. The NACC UDS brief TBI screen missed 50% of TBI exposures identified using the OSU TBI-ID interview. Conclusion: The OSU TBI-ID interview and web-based survey may facilitate more accurate TBI exposure classification in cognitive aging research thereby accelerating discovery of targetable mechanisms of post-TBI dementia.