Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Amen, Daniel G. | Wu, Joseph | George, Noble | Newberg, Andrew

Article Type: Research Article

Abstract: Background: While obesity has been shown to be a risk factor for Alzheimer’s disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons. Objective: To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status. Methods: A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8±16.2 years, range 18–94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous …Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI≥30), and morbid obesity (BMI≥40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas. Results: Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus. Conclusion: Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood. Show more

Keywords: Cerebral perfusion, obesity, SPECT

DOI: 10.3233/JAD-200655

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. Objective: Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. Methods: We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation …was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naïve subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Results: Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11–1.31] and lower probability of DPP-4i (0.72 [0.66–0.79]), GLP-1a (0.51 [0.41–0.63]), and SGLT-2i dispensation (0.44 [0.36–0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (–0.58%), GLP-1a (–0.13%), and SGLT-2i (–0.21%) dispensation in dementia patients compared to dementia-free controls. Conclusion: Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects. Show more

Keywords: Dementia, diabetes mellitus, hypoglycemic agents, pharmacoepidemiology

DOI: 10.3233/JAD-200618

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Hasegawa, Tohru | Kosoku, Yoshinori | Sano, Yuka | Yoshida, Hiroshi | Kudoh, Chiaki | Tabira, Takeshi

Article Type: Research Article

Abstract: Background: In the treatment of Alzheimer’s disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD. Objective: Homocysteic acid (HCA) is useful as an …early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. Methods: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients’ plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. Results: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μ M was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. Conclusion: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD. Show more

Keywords: Alzheimer disease, homocysteic acid, mild cognitive impairment, plasma

DOI: 10.3233/JAD-200234

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Silverman, Hannah E. | Gazes, Yunglin | Barker, Megan S. | Manoochehri, Masood | Goldman, Jill S. | Wassermann, Eric M. | Tierney, Michael C. | Cosentino, Stephanie | Grafman, Jordan | Huey, Edward D.

Article Type: Research Article

Abstract: Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography …(18 FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p  = 0.009] and NC [p  < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p  = 0.026] and NC [p  < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors [p  < 0.01]. Hypometabolism in Brodmann’s Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p (FWE-corr) <0.05, k  = 44]. No anatomical associations were found with other sexual changes. Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction. Show more

Keywords: Frontal lobe, frontotemporal dementia, neurodegenerative disorders, prefrontal cortex, sexual behavior

DOI: 10.3233/JAD-200346

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Mar, Javier | Gorostiza, Ania | Ibarrondo, Oliver | Cernuda, Carlos | Arrospide, Arantzazu | Iruin, Álvaro | Larrañaga, Igor | Tainta, Mikel | Ezpeleta, Enaitz | Alberdi, Ane

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are the leading cause of the social burden of dementia but their role is underestimated. Objective: The objective of the study was to validate predictive models to separately identify psychotic and depressive symptoms in patients diagnosed with dementia using clinical databases representing the whole population to inform decision-makers. Methods: First, we searched the electronic health records of 4,003 patients with dementia to identify NPS. Second, machine learning (random forest) algorithms were applied to build separate predictive models for psychotic and depressive symptom clusters in the training set (N = 3,003). Third, calibration and discrimination …were assessed in the test set (N = 1,000) to assess the performance of the models. Results: Neuropsychiatric symptoms were noted in the electronic health record of 58% of patients. The area under the receiver operating curve reached 0.80 for the psychotic cluster model and 0.74 for the depressive cluster model. The Kappa index and accuracy also showed better discrimination in the psychotic model. Calibration plots indicated that both types of model had less predictive accuracy when the probability of neuropsychiatric symptoms was <25%. The most important variables in the psychotic cluster model were use of risperidone, level of sedation, use of quetiapine and haloperidol and the number of antipsychotics prescribed. In the depressive cluster model, the most important variables were number of antidepressants prescribed, escitalopram use, level of sedation, and age. Conclusion: Given their relatively good performance, the predictive models can be used to estimate prevalence of NPS in population databases. Show more

Keywords: Dementia, depressive symptoms, machine learning, neuropsychiatric symptoms, predictive model\sep prevalence, psychotic symptoms, real-world data

DOI: 10.3233/JAD-200345

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Gonzlez, Andrea | Guzmn-Martínez, Leonardo | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Background: A major drawback in Alzheimer’s disease (AD) is the lack of validated biomarkers for routine clinical diagnostic. We have reported earlier a novel blood biomarker, named Alz-tau® , based on variants of platelet tau. This marker evaluates the ratio of high molecular weight tau (HMWtau) and the low molecular weight (LMWtau) tau. Objective: To analyze a potential novel source of antigen for Alz-tau® , plasma tau, detected by immunoreactivity with the novel monoclonal antibody, tau51. Methods: We evaluated tau variants in plasma precipitated with ammonium sulfate from 36 AD patients and 15 control subjects by …western blot with this novel monoclonal antibody. Results: The HMW/LMWtau ratio was statistically different between AD patients and controls. Conclusions: Plasma tau variants are suitable to be considered as a novel antigen source for the Alz-tau® biomarker for AD. Show more

Keywords: Alz-tau®, Alzheimer’s disease, HMW/LMWtau ratio, monoclonal antibodies, peripheral biomarkers, tau protein in the human plasma

DOI: 10.3233/JAD-200386

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Wang, Yan-Juan | Gong, Wei-Gang | Ren, Qing-Guo | Zhang, Zhi-Jun

Article Type: Research Article

Abstract: Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro . Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. …Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway. Show more

Keywords: Alzheimer’s disease, selective serotonin reuptake inhibitor, synapse, tau hyperphosphorylation, transgenic mice

DOI: 10.3233/JAD-200401

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Aksnes, Mari | Müller, Ebba Glersen | Tiiman, Ann | Edwin, Trine Holt | Terenius, Lars | Revheim, Mona-Elisabeth | Vukojević, Vladana | Bogdanović, Nenad | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Aggregation of amyloid-β (Aβ ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18 F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF …from 54 memory clinic patients were compared between sub-groups classified by 18 F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptides, amyloidogenic proteins, biomarkers, cerebrospinal fluid, fluorescence spectrometry, positron-emission tomography, Thioflavin T

DOI: 10.3233/JAD-200237

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Rao, Shalini S. | Portbury, Stuart. D. | Lago, Larissa | Bush, Ashley I. | Adlard, Paul A.

Article Type: Research Article

Abstract: Background: Abnormally hyperphosphorylated tau is a defining pathological feature of tauopathies, such as Alzheimer’s disease (AD), and accumulating evidence suggests a role for iron in mediating tau pathology that may lead to cognitive decline in these conditions. The metal chelator deferiprone (DFP), which has a high affinity for iron, is currently in clinical trials for AD and Parkinson’s disease. However, the effect of DFP on tau pathology remains underexplored. Objective: We aimed to investigate the impact of chronic DFP treatment on tau pathology using a well-characterized mouse model of tauopathy (rTg(tauP301L )4510). Methods: Animals were treated …daily with DFP (100 mg/kg) via oral gavage for 16 weeks. After 14 weeks, mice were tested in the Y-maze, open field, Morris water maze, and rotorod. At the end of the study, brain tissue was collected to examine metal levels (using inductively coupled plasma-mass spectrometry) and for western blot analysis of DFP on tau and iron associated pathways. Results: DFP significantly reduced anxiety-like behavior, and revealed a trend toward improved cognitive function. This was accompanied by a decrease in brain iron levels and sarkosyl-insoluble tau. Our data also showed downregulation of the tau kinases glycogen synthase kinase 3β and cyclin dependent kinase-5 in DFP treated mice and an increase in the methylation of the catalytic subunit of protein phosphatase 2A. Conclusion: These data support the hypothesis that suggests that iron plays a neurotoxic role in tauopathies and may be a potential therapeutic target for this class of disorders. Show more

Keywords: Alzheimer’s disease, deferiprone, iron, tau proteins, tauopathies, therapeutic

DOI: 10.3233/JAD-200551

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Furtado, André | Astaburuaga, Rosario | Costa, Ana | Duarte, Ana C. | Gonçalves, Isabel | Cipolla-Neto, José | Lemos, Manuel C. | Carro, Eva | Relógio, Angela | Santos, Cecília R.A. | Quintela, Telma

Article Type: Research Article

Abstract: Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before …amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2 ) expression in male mice. Besides, a significant circadian pattern of Bmal1 occurs in the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood-cerebrospinal fluid barrier, choroid plexus, circadian clock, melatonin

DOI: 10.3233/JAD-200331

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Zhang, Chenbo | Luo, Jianfeng | Yuan, Changzheng | Ding, Ding

Article Type: Research Article

Abstract: Background: Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. Objective: To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. Methods: Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake …levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. Results: Twenty-one observational studies with sample sizes ranging from 155– 7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61– 0.97) and folate concentration (OR = 0.68, 95% CI = 0.51– 0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. Conclusion: The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, folate, nutrition, vitamin B6, vitamin B12

DOI: 10.3233/JAD-200534

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Caligiore, Daniele | Silvetti, Massimo | D’Amelio, Marcello | Puglisi-Allegra, Stefano | Baldassarre, Gianluca

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and …neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions. Show more

Keywords: Alzheimer’s disease, anterior cingulate cortex, apathy, decision-making, dopamine, effort, locus coeruleus, meta-learning, norepinephrine, pre-plaque stage, reinforcement learning, reinforcement meta-learner, ventral tegmental area

DOI: 10.3233/JAD-200276

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Kim, Jieun | Lee, Yujeong | Lee, Seulah | Kim, Kipom | Song, Minjung | Lee, Jaewon

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease worldwide, but its cause remains unclear. Although a few drugs can provide temporary and partial relief of symptoms in some patients, no curative treatment is available. Therefore, attention has been focused on research using stem cells to treat AD. Among stem cells, mesenchymal stem cells (MSCs) have been used to treat the related pathologies in animal models of AD, and other neurodegenerative disease. This review describes latest research trends on the use of MSC-based therapies in AD and its action of mechanism. MSCs have several beneficial effects. They would be …specified as the reduction of neuroinflammation, the elimination of amyloid-β, neurofibrillary tangles, and abnormal protein degradation, the promotion of autophagy-associated and blood-brain barrier recoveries, the upregulation of acetylcholine levels, improved cognition, and the recovery of mitochondrial transport. Therefore, this review describes the latest research trends in MSC-based therapy for AD by demonstrating the importance of MSC-based therapy and understanding of its mechanisms in AD and discusses the limitations and perspectives of stem cell therapy in AD. Show more

Keywords: Alzheimer’s disease, mesenchymal stem cells, stem cell therapy

DOI: 10.3233/JAD-200219

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Xu, Anping | Tang, Yinshan | Zeng, Qingtao | Wang, Xin | Tian, Huiling | Zhou, You | Li, Zhigang

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease, yet there is no effective treatment. Electroacupuncture (EA) is a complementary alternative medicine approach. In clinical and animal studies, EA promotes cognition in AD and vascular dementia. It has been previously reported that cognitive decline in AD might be closely related to reduced glucose intake in the brain. It is worth mentioning that the regions of glucose hypometabolism are usually found to be associated with neuroinflammation. Objective: This study is to explore whether the protective mechanism of EA on cognition is related to the regulation of glucose metabolism and neuroinflammation. …Methods: APP/PS1 mice were randomly divided into AD group and the treatment (AD + EA) group. In the AD + EA group, EA was applied on Baihui (GV20) and Yintang (GV29) for 20 min and then pricked at Shuigou (GV26), once every alternate day for 4 weeks. Morris water maze (MWM) tests were performed to evaluate the effects of EA treatment on cognitive functions. 18 F-FDG PET, immunofluorescence, and western blot were used to examine the mechanisms underlying EA effects. Results: From MWM tests, EA treatment significantly improved cognition of APP/PS1 mice. From the 18 F-FDG PET, the levels of uptake rate of glucose in frontal lobe were higher than the AD group after EA. From immunofluorescence and western blot, amyloid-β (Aβ) and neuroinflammation were reduced after EA. Conclusion: These results suggest that EA may prevent cognitive decline in AD mouse models by enhancing glucose metabolism and inhibiting inflammation-mediated Aβ deposition in the frontal lobe. Show more

Keywords: Alzheimer’s disease, cognition, electroacupuncture, 18F-FDG PET, frontal lobe, glucose metabolism, neuroinflammation

DOI: 10.3233/JAD-200242

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Schneider, Julia | Schönstein, Anton | Teschauer, Winfried | Kruse, Andreas | Teichmann, Birgit

Article Type: Research Article

Abstract: Background: The outcomes of hospitalized People with Dementia (PwD) are likely to be negative due to, among other key causes, negative staff attitudes and limited staff knowledge regarding dementia. Targeted interventions have been shown to positively change the attitudes of the hospital staff while also increasing their overall knowledge of dementia. However, training effects are often short-lived and frequently long-term effects are not examined in studies. Objective: To examine whether attending a dementia training program changes the attitudes of hospital staff toward PwD and/or increases their knowledge levels about dementia, and whether or not these changes are stable. …Methods: The training program lasted two days and N  = 60 attending hospital staff members agreed to participate in the study. Data were assessed with questionnaires prior to the training, 3 months, and 6 months after the training. German versions of the Dementia Attitude Scale (DAS-D) and the Knowledge in Dementia (KIDE) scale were used. Additionally, data about perception of PwD and confidence in dealing with challenging behavior were collected and analyzed. Results: After the training program, participants showed a significantly better attitude toward PwD as measured by DAS-D. These time-effects occurred in both DAS-D subscales (“dementia knowledge” and “social comfort”). Although a positive trend could be seen in the KIDE scale, no statistically significant increase occurred over time. Conclusion: Specialist training programs seem to be promising in positively changing attitudes toward and increasing knowledge about PwD with long-term effects. Further research should address the effects of attitude change in patient care. Show more

Keywords: Education, health facilities, health personnel, neurocognitive disorders, staff development

DOI: 10.3233/JAD-200268

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Lepper, Simon | Rädke, Anika | Wehrmann, Hannah | Michalowsky, Bernhard | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Treatment decisions based on guidelines rather than patients’ preferences determine adherence to and compliance with treatment, which, in turn, could improve health-related outcomes. Objectives: To summarize the stated treatment and care preferences of people with dementia (PwD). Methods: A systematic review was conducted to assess the stated preferences of PwD. The inclusion criterion was the use of quantitative methods to elicit stated preferences, enabling a ranking of preferences. Results: Eleven studies revealed preferences for diagnostics, treatment decisions, patient-related outcomes, care services, end-of-life care, leisure activities, and digital life story work. PwDs prefer accurate, …pain-free, and comfortable diagnostic procedures without radioactive markers as well as being accompanied by a caregiver. PwD’s quality of life (QoL), self-efficacy, and depression were equally most important for PwD and caregivers. However, PwD memory was only important for caregivers but not for PwD, and caregiver QoL was moderately important for PwD but least important for caregivers. Additionally, comfort and family involvement were most important for patients’ end-of-life care, whereas caregivers most preferred good communication and pain management. Also, preferences depend on the living situation: Patients living not alone prefer a regular care provider most, whereas those living alone only want to live nearby the caregiver. Preferences for leisure activities did not differ between past and present ratings, indicating that PwD prefer activities that have always been carried out. Conclusion: Only a few studies have applied quantitative methods to elicit the preferences of PwD. More research is needed to capture the stated preferences for the treatment, care, and support of PwD to improve health-related outcomes and the allocation of healthcare resources. Show more

Keywords: Dementia, decision making, patient outcome assessment, patient preference

DOI: 10.3233/JAD-191299

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Hu, Li | Zhu, Shaoping | Peng, Xiaoping | Li, Kanglan | Peng, Wanjuan | Zhong, Yu | Kang, Chenyao | Cao, Xingxing | Liu, Zhou | Zhao, Bin

Article Type: Research Article

Abstract: Background: Excessive salt intake is considered an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. Objective: To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Methods: Adult female C57BL6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. …Results: The mice fed an HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β , IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. Conclusion: The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production. Show more

Keywords: Blood-brain barrier, cognition, gut microbiota, high-salt diet, microglia, short-chain fatty acids

DOI: 10.3233/JAD-200035

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Sheng, Can | Yang, Kun | Wang, Xiaoni | Li, Hongyan | Li, Taoran | Lin, Li | Liu, Yi | Yang, Qin | Wang, Xiaoqi | Wang, Xue | Sun, Yu | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered the earliest symptomatic manifestation of preclinical Alzheimer’s disease (AD). Currently, given the lack of effective and curable pharmacological treatments for AD, non-pharmacological interventions (NPIs) for individuals with SCD may provide a valuable opportunity for the secondary prevention of AD. Objective: This systematic review and meta-analysis, conducted in accordance with the PRISMA guidelines, aimed to investigate the benefits of current NPIs in the population with SCD. Methods: The online electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, PsycInfo, and CINAHL, were searched to identify randomized controlled trials …of NPIs for SCD. Intervention strategies were psychological and health-related education interventions, mind-body therapy, lifestyle modification, cognitive training, and multidomain interventions. Outcomes included subjective memory, objective memory, global cognitive function, psychological well-being, and mood. Study quality was determined using the criteria of the Cochrane collaboration’s tool. The Hedges’ g of change was analyzed. Results: Eighteen studies were included in this review and meta-analysis. Overall, psychological and health-related education interventions exhibited a medium effect on objective memory function (Hedges’ g  = 0.53, p  = 0.01). Cognitive training led to a small effect on objective memory, which was marginal statistically (Hedges’ g  = 0.19, p  = 0.05). In addition, cognitive training also significantly improved subjective memory performance (Hedges’ g  = 0.49, p  = 0.0003) and psychological well-being (Hedges’ g  = 0.27, p  = 0.03). Conclusion: Overall, the psychological intervention and cognitive training may be beneficial to cognitive function and psychological well-being. NPIs may be effectively implemented in older adults with SCD. Show more

Keywords: Alzheimer’s disease, cognitive training, intervention, lifestyle, non-pharmacological, psychological, subjective cognitive decline

DOI: 10.3233/JAD-191295

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: de Leeuw, Francisca A. | Honer, William G. | Schneider, Julie A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Background: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. Objective: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. Methods: We examined associations of α - and γ -tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a …SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. Results: Higher brain γ -tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p  < 0.001 to 0.003). When additionally adjusted for global Alzheimer’s disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α -tocopherol and presynaptic protein levels. Conclusion: In this cross-sectional study, we found higher brain γ -tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels. Show more

Keywords: Antioxidants, SNARE protein, tocopherols, vitamin E

DOI: 10.3233/JAD-200166

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Trammell, Antoine R. | McDaniel, Darius J. | Obideen, Malik | Okafor, Maureen | Thomas, Tiffany L. | Goldstein, Felicia C. | Shaw, Leslie M. | Hajjar, Ihab M.

Article Type: Research Article

Abstract: Background: African Americans (AA) have a higher Alzheimer’s disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. Objective: Establish biomarker evidence for the observed association between stress and AD, especially in AA. Methods: A cross-sectional study (n  = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n  = 309) provided cerebrospinal fluid for measurement of Aβ 42 , Tau, Ptau, Tau/Aβ 42 (TAR), and Ptau/Aβ …42 (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed. Results: Higher PSS scores were associated with higher Ptau (β = 0.43, p  = 0.01) and PTAR (β = 0.005, p  = 0.03) in AA with impaired cognition (mild cognitive impairment). Conclusion: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity. Show more

Keywords: African Americans, Alzheimer’s disease, tauopathy, amyloid-β peptides, cognitive function, mild cognitive impairment, neurocognitive tests, psychological stress

DOI: 10.3233/JAD-200089

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Tan, Ji-Ping | Wang, Xiaoxiao | Lan, Xiaoyang | Li, Nan | Zhang, Shimin | Zhao, Yiming | Wang, Lu-Ning

Article Type: Research Article

Abstract: Background: Over time, improved cognitive abilities in elderly individuals lead to an overall increase in performance on widely used cognitive screening tests (e.g., Mini-Mental State Examination, MMSE) and impact screening efficacy. Objective: We aimed to examine the epoch effect on cognitive function measured using MMSE, in addition to the influence of demographic characteristics on MMSE. We also evaluated the ability of the MMSE in detecting dementia and examined the discrimination ability and measurement precision of the MMSE. Methods: In a cross-sectional survey, Chinese veterans aged ≥60 years were interviewed. Multiple linear regression analysis was applied to …explore the factors affecting the MMSE. The expected MMSE score was calculated to examine the epoch effect. The diagnostic accuracy of the MMSE was determined via receiver operating characteristic curve analyses. Item response theory methods were implemented using Stata 16.0. Results: The MMSE score increased with higher education and decreased with advancing age. The observed MMSE score in this study (26.9) was higher than the expected MMSE score (24.9). It demonstrated 78.3% /84.1% /89.9% sensitivity and 85.8% /79.5% /66.8% specificity in detecting dementia using the cut-off score 25/26/27. The MMSE showed reduced discrimination and provided little information for ability level of −1 and above. Conclusion: Improved cognitive ability over time may increase the performance on cognitive screening tests (e.g., MMSE). This impact of epoch in cognitive function emphasizes the importance of regularly updating cognitive screening tests. Show more

Keywords: Dementia, epoch effect, item response theory, Mini-Mental State Examination

DOI: 10.3233/JAD-200112

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Lamballais, Sander | Zijlmans, Jendé L. | Vernooij, Meike W. | Ikram, M. Kamran | Luik, Annemarie I. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Individual differences in the risk to develop dementia remain poorly understood. These differences may partly be explained through reserve, which is the ability to buffer cognitive decline due to neuropathology and age. Objective: To determine how much early and late–life cognitive reserve (CR) and brain reserve (BR) contribute to the risk of dementia. Methods: 4,112 dementia-free participants (mean age = 66.3 years) from the Rotterdam Study were followed up for on average 6.0 years. Early-life CR and BR were defined as attained education and intracranial volume, respectively. Late-life CR was derived through variance decomposition based on cognition. …Late-life BR was set as the total non-lesioned brain volume divided by intracranial volume. Results: Higher early-life CR (hazard ratio = 0.48, 95% CI = [0.21; 1.06]) but not early-life BR associated with a lower risk of incident dementia. Higher late-life CR (hazard ratio = 0.57, 95% CI = [0.48; 0.68]) and late-life BR (hazard ratio = 0.54, 95% CI = [0.43; 0.68]) also showed lower levels of dementia. Combining all proxies into one model attenuated the association between early-life CR and dementia (hazard ratio = 0.56, 95% CI = [0.25; 1.25]) whereas the other associations were unaffected. These findings were stable upon stratification for sex, age, and APOE ɛ 4. Finally, high levels of late-life CR and BR provided additive protection against dementia. Conclusion: The findings illustrate the importance of late-life over early-life reserve in understanding the risk of dementia, and show the need to study CR and BR conjointly. Show more

Keywords: Cognition, cognitive reserve, dementia, education, neuroimaging

DOI: 10.3233/JAD-200264

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Caruso, Giulia | Perri, Roberta | Fadda, Lucia | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Background: It has long been debated whether performance on recall and recognition tests depends on the same or different memory systems and whether performance on these two tasks is dissociated in clinical populations. According to Dual process theories of recall , performance on recall and recognition tests dissociates in the relative reliance on frontal lobe related activities; in fact, the recall test requires more strategic retrieval of memoranda than the recognition task. By contrast, Dual process theories of recognition posit that performance on these tests differs in the relative contribution of recollection and familiarity memory processes in the two …tasks: both recollection and familiarity contribute to recognition judgments, but only recollection supports recall performance. Objective: The aim of this study was to clarify the cognitive processes involved in recall and recognition in patients with dementia. Methods: We administered a 15-word recall task followed by a yes/no recognition paradigm to 28 patients with Alzheimer’s disease (AD), 22 patients with the behavioral variant of frontotemporal dementia (bvFTD), and 45 normal controls (NCs). Results: Results showed that on the delayed recall task, bvFTD patients performed much better than AD patients but the two groups did not differ on any index of recognition performance. Conclusion: The present data support the hypothesis that the performance of the two groups is expression of the different reliance on recollection (more impaired in the AD than in the bvFTD group) and familiarity (similarly impaired in the two groups) in performance on recall and recognition tasks. Show more

Keywords: Alzheimer’s disease, familiarity, frontotemporal dementia, recall, recognition, recollection

DOI: 10.3233/JAD-200126

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Keleman, Audrey | Wisch, Julie K. | Bollinger, Rebecca M. | Grant, Elizabeth A. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n  = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, …and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p  = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = –0.75, p  = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p  = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD. Show more

Keywords: Alzheimer’s disease, biomarkers, falls, resting state functional connectivity, volumetrics

DOI: 10.3233/JAD-200192

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Monsees, Jessica | Schmachtenberg, Tim | Hoffmann, Wolfgang | Kind, Amy | Gilmore-Bykovskyi, Andrea | Kim, Alice J. | Thyrian, Jochen René

Article Type: Research Article

Abstract: Background: As the proportion of older people with migration background (PwM) increases, the proportion of older PwM with dementia might also increase. Dementia is underdiagnosed in this group and a large proportion of PwM with dementia and family caregivers are not properly supported. Healthcare utilization is lower among older migrant populations. Thus, a better understanding of how PwM and family caregivers perceive their situation and how they experience healthcare services is needed to improve utilization of the healthcare system. Objective: Analyze how family caregivers of PwM with dementia experience their situation, why healthcare services are utilized less often, …and what can be done to reverse this. Methods: Eight semi-structured interviews were conducted with people with Turkish migration background caring for PwM with dementia. Qualitative content analysis was used for data analysis. Results: Daily care was performed by one family member with the support of others. Healthcare services were used by most participants. Participants identified a need for better access to relevant information and incorporation of Turkish culture into healthcare services. Conclusion: PwM face similar challenges in taking care of persons with dementia as those without migration background. There is a willingness to use services, and services embracing Turkish culture would help to reduce hesitance and make affected people feel more comfortable, thereby increasing utilization and satisfaction. A limitation of this study is that participants were already connected to health services, which may not reflect the help-seeking behavior of those in the Turkish community who are not involved in healthcare. Show more

Keywords: Dementia, healthcare, healthcare services, migration, Turkish migration background, utilization

DOI: 10.3233/JAD-200184

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Pedrini, Steve | Hone, Eugene | Gupta, Veer B. | James, Ian | Teimouri, Elham | Bush, Ashley I. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Masters, Colin L. | Rainey-Smith, Stephanie | Verdile, Giuseppe | Sohrabi, Hamid R. | Raida, Manfred R. | Wenk, Markus R. | Taddei, Kevin | Chatterjee, Pratishtha | Martins, Ian | Laws, Simon M. | Martins, Ralph N. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: The link between cholesterol and Alzheimer’s disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a “good” lipid complex due to its ability to enable clearance of excess cholesterol via ‘cholesterol reverse transport’, although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly …formed small HDL, to much larger HDL. Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ ) levels or brain Aβ deposition. Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ 1–42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances. Show more

Keywords: Amyloid-β, apolipoprotein, blood, cholesterol, lipid transport

DOI: 10.3233/JAD-200291

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Garrido, Sandra | Dunne, Laura | Stevens, Catherine J. | Chang, Esther | Clements-Cortes, Amy

Article Type: Research Article

Abstract: Background: Music programs have the potential to provide an effective non-pharmacological tool for caregivers to reduce depression and agitation and increase quality of life in people with dementia. However, where such programs are not facilitated by a trained music therapist, caregivers need greater access to information about how to use music most effectively in response to key challenges to care, and how to pre-empt and manage adverse responses. Objective: This study reports on the trial of a Guide for use of music with 45 people with dementia and their caregivers in residential care facilities and home-based care. …Methods: The study used a pre-post experimental design in which participants were randomly allocated to a treatment group or a waitlist control group. Results: Improvements to quality of life were found in the experimental group over the 6-week period. Significant increases in Interest, Responsiveness, Initiation, Involvement, and Enjoyment were reported for individual listening sessions. Conclusion: The Guide can provide an effective protocol for caregivers to follow in selecting music to manage particular challenges to care, confirming the need for caregivers to be prepared to monitor and manage potential negative responses. Show more

Keywords: Aged care, agitation, Alzheimer’s disease, arts-based therapies, geriatric depression, health guidelines

DOI: 10.3233/JAD-200457

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Fung, Susan | Smith, Carole L. | Prater, Katherine E. | Case, Amanda | Green, Kevin | Osnis, Leah | Winston, Chloe | Kinoshita, Yoshito | Sopher, Bryce | Morrison, Richard S. | Garden, Gwenn A. | Jayadev, Suman

Article Type: Research Article

Abstract: Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1 ), presenilin 2 (PSEN 2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer’s disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration. Accumulating evidence suggests that microglia, resident innate immune cells in the central nervous system, play a key role in AD neurodegeneration. …Objective: Previous work has identified a regulatory role for PS2 in microglia. We hypothesized that PSEN2 variants lead to dysregulated microglia, which could further contribute to disease acceleration. To mimic the genotype of EOFAD patients, we created a transgenic mouse expressing PSEN2 N141I on a mouse background expressing one wildtype PS2 and two PS1 alleles. Results: Microglial expression of PSEN2 N141I resulted in impaired γ -secretase activity as well as exaggerated inflammatory cytokine release, NFκ B activity, and Aβ internalization. In vivo , PS2 N141I mice showed enhanced IL-6 and TREM2 expression in brain as well as reduced branch number and length, an indication of “activated” morphology, in the absence of inflammatory stimuli. LPS intraperitoneal injection resulted in higher inflammatory gene expression in PS2 N141I mice brain relative to controls. Conclusion: Our findings demonstrate that PSEN2 N141I heterozygosity is associated with disrupted innate immune homeostasis, suggesting EOFAD variants may promote disease progression through non-neuronal cells beyond canonical dysregulated Aβ production. Show more

Keywords: Alzheimer’s disease, cytokine, glia, inflammation, microglia, phagocytosis, presenilin

DOI: 10.3233/JAD-200492

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Gallucci, Maurizio | Mazzarolo, Anna Paola | Focella, Lucia | Piovesan, Cinzia | Mazzetto, Manuela | Ramigni, Mauro | Marzetti, Emanuele

Article Type: Research Article

Abstract: Background: Frailty is a condition of increased vulnerability to exogenous and endogenous stressors, which is correlated with aging, functional decline, institutionalization, hospitalization, and mortality. Given the multifaceted nature of frailty, programs aimed at its prevention are recommended to act on multiple domains. Objective: The present intervention program aimed at assessing the effects of combined physical and cognitive training in older people with mild cognitive impairment (MCI) and at investigating how their frailty status changed over one year of follow-up. Methods: Two-hundred and seven participants were recruited among outpatients of the Cognitive Impairment Center who agreed to …receive a comprehensive assessment. Forty-six participants, who joined a structured program of physical activity and group readings for a period of one year, were defined as active. The remaining 161, who decided not to engage in those activities, were considered controls. In both groups, frailty status was assessed at baseline and over one year of follow-up. Results: Control participants showed twice the risk of becoming frail at 12 months compared with those in the active group. Participants in the active group had more than three times the probability of improving their frailty status compared with the control group from T0 to T12. Age and NPI scores were significantly associated with worsening frailty status. When analyses were restricted to participants who were robust at baseline, the frailty status varied significantly between groups over time. Conclusion: Findings of the present study confirm the beneficial effects of physical activity and reading to prevent frailty in older people with MCI. Show more

Keywords: Cognitive frailty, community, multi-domain intervention, neuroimaging, TREDEM registry

DOI: 10.3233/JAD-200542

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Poptsi, Eleni | Moraitou, Despina | Tsardoulias, Emmanouil | Symeonidisd, Andreas L. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The early diagnosis of neurocognitive disorders before the symptoms’ onset is the ultimate goal of the scientific community. REMEDES for Alzheimer (R4Alz) is a battery, designed for assessing cognitive control abilities in people with minor and major neurocognitive disorders. Objective: To investigate whether the R4Alz battery’s tasks differentiate subjective cognitive decline (SCD) from cognitively healthy adults (CHA) and mild cognitive impairment (MCI). Methods: The R4Alz battery was administered to 175 Greek adults, categorized in five groups a) healthy young adults (n  = 42), b) healthy middle-aged adults (n  = 33), c) healthy older adults (HOA; n  = 14), …d) community-dwelling older adults with SCD (n  = 34), and e) people with MCI (n  = 52). Results: Between the seven R4Alz subtasks, four showcased the best results for differentiating HOA from SCD: the working memory updating (WMCUT-S3), the inhibition and switching subtask (ICT/RST-S1&S2), the failure sets (FS) of the ICT/RST-S1&S2, and the cognitive flexibility subtask (ICT/RST-S3). The total score of the four R4Alz subtasks (R4AlzTot4) leads to an excellent discrimination among SCD and healthy adulthood, and to fare discrimination among SCD and MCI. Conclusion: The R4Alz battery is a novel approach regarding the neuropsychological assessment of people with SCD, since it can very well assist toward discriminating SCD from HOA. The R4Alz is able to measure decline of specific cognitive control abilities—namely of working memory updating, and complex executive functions—which seem to be the neuropsychological substrate of cognitive complaints in community dwelling adults of advancing age. Show more

Keywords: Cognitive control assessment battery, cognitively healthy adults, mild cognitive impairment, normative data, subjective cognitive decline

DOI: 10.3233/JAD-200562

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Badji, Atef | de la Colina, Adrián Noriega | Boshkovski, Tommy | Sabra, Dalia | Karakuzu, Agah | Robitaille-Grou, Marie-Christine | Gros, Charley | Joubert, Sven | Bherer, Louis | Lamarre-cliche, Maxime | Stikov, Nikola | Gauthier, Claudine J. | Cohen-Adad, Julien | Girouard, Hélène

Article Type: Research Article

Abstract: Background: Vascular risk factors such as arterial stiffness play an important role in the etiology of Alzheimer’s disease (AD), presumably due to the emergence of white matter lesions. However, the impact of arterial stiffness to white matter structure involved in the etiology of AD, including the corpus callosum remains poorly understood. Objective: The aims of the study are to better understand the relationship between arterial stiffness, white matter microstructure, and perfusion of the corpus callosum in older adults. Methods: Arterial stiffness was estimated using the gold standard measure of carotid-femoral pulse wave velocity (cfPWV). Cognitive performance …was evaluated with the Trail Making Test part B-A. Neurite orientation dispersion and density imaging was used to obtain microstructural information such as neurite density and extracellular water diffusion. The cerebral blood flow was estimated using arterial spin labelling. Results: cfPWV better predicts the microstructural integrity of the corpus callosum when compared with other index of vascular aging (the augmentation index, the systolic blood pressure, and the pulse pressure). In particular, significant associations were found between the cfPWV, an alteration of the extracellular water diffusion, and a neuronal density increase in the body of the corpus callosum which was also correlated with the performance in cognitive flexibility. Conclusion: Our results suggest that arterial stiffness is associated with an alteration of brain integrity which impacts cognitive function in older adults. Show more

Keywords: Aging, Alzheimer’s disease, arterial spin labelling, arterial stiffness, corpus callosum, diffusion weighted imaging

DOI: 10.3233/JAD-200668

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Fu, Pengfei | Yung, Ken Kin Lam

Article Type: Research Article

Abstract: Background: Ambient air pollution has been associated with Alzheimer’s disease (AD) in the elderly. However, its effects on AD have not been meta-analyzed comprehensively. Objective: We conducted a systematic review and meta-analysis to assess the associations between air pollution and AD incidence. Methods: We searched PubMed and Web of Science for indexed publications up to March 2020. Odds risk (OR) and confidence intervals (CI) were estimated for particulate matter (PM)10 (PM10 ), PM2.5 , ozone (O3 ), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and carbon monoxide (CO). The subgroup analysis was conducted based on …the pollution levels. Results: Nine studies were included in the meta-analysis and review. The OR per 10μ g/m3 increase of PM2.5 was 1.95 (95% CI: 0.88–4.30). The corresponding values per 10μ g/m3 increment of other pollutants were 1.03 (95% CI: 0.68–1.57) for O3 , 1.00 (95% CI: 0.89–1.13) for NO2 , and 0.95 (95% CI: 0.91–0.99) for PM10 (only one study), respectively. Overall OR of the five air pollutants above with AD was 1.32 (95% CI: 1.09–1.61), suggesting a positive association between ambient air pollution and AD incidence. The sub-analysis indicated that the OR (2.20) in heavily polluted regions was notably higher than that in lightly polluted regions (1.06). Although AD risk rate data related to SO2 or CO exposure are still limited, the epidemiologic and toxicological evidence indicated that higher concentration of SO2 or CO exposure increased risks of dementia, implying that SO2 or CO might have a potential impact on AD. Conclusion: Air pollution exposure may exacerbate AD development. Show more

Keywords: Air pollution, Alzheimer’s disease, meta-analysis, systematic review

DOI: 10.3233/JAD-200483

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Junquera Fernández, Almudena | García-Zamora, Estefanía | Olazarán Rodríguez, Javier | Parra Rodríguez, Mario A. | Fernández-Guinea, Sara

Article Type: Research Article

Abstract: Background: Recent research pointed to executive dysfunction as a potential early predictor of the progression of mild cognitive impairment (MCI)–dementia in Alzheimer’s clinical syndrome (ACS). Such cognitive impairments account for functional impairments in instrumental activities of daily living (IADL). Objective: The present study analyzes the contributions of executive functions to predict MCI–dementia progression in ACS. Methods: We assessed 145 participants, 51 cognitively unimpaired and 94 MCI. The latter were divided using the traditional, memory-based MCI classification (single domain amnestic, multidomain amnestic, and non-amnestic). Eight tests assessing executive functions were administered at baseline and at 1-year follow-up, …together with cognitive screening tools and IADL measures. MCI patients were reclassified based on the outcomes from a K-mean cluster analysis which identified three groups. A simple lineal regression model was used to examine whether the classification based on executive functioning could more accurately predict progression to dementia a year later. Results: Clusters based on executive function deficits explained a significant proportion of the variance linked to MCI–dementia conversion, even after controlling for the severity of MCI at baseline (F (1, 68) = 116.25, p  = 0.000, R2  = 0.63). Classical memory-based MCI classification failed to predict such a conversion (F (1, 68) = 5.09, p  = 0.955, R2  = 0.07). Switching, categories generation, and planning were the executive functions that best distinguished between MCI converters and stable. Conclusion: MCI with a dysexecutive phenotype significantly predicts conversion to dementia in ACS a year later. Switching abilities and verbal fluency (categories) must be evaluated in MCI patients to assess risk of future dementia. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive dysfunction, executive function, longitudinal studies

DOI: 10.3233/JAD-200586

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: McKeown, Alex | Turner, Andrew | Angehrn, Zuzanna | Gove, Dianne | Ly, Amanda | Nordon, Clementine | Nelson, Mia | Tochel, Claire | Mittelstadt, Brent | Keenan, Alex | Smith, Michael | Singh, Ilina

Article Type: Research Article

Abstract: Background: Dementia has been described as the greatest global health challenge in the 21st century on account of longevity gains increasing its incidence, escalating health and social care pressures. These pressures highlight ethical, social, and political challenges about healthcare resource allocation, what health improvements matter to patients, and how they are measured. This study highlights the complexity of the ethical landscape, relating particularly to the balances that need to be struck when allocating resources; when measuring and prioritizing outcomes; and when individual preferences are sought. Objective: Health outcome prioritization is the ranking in order of desirability or importance …of a set of disease-related objectives and their associated cost or risk. We analyze the complex ethical landscape in which this takes place in the most common dementia, Alzheimer’s disease. Methods: Narrative review of literature published since 2007, incorporating snowball sampling where necessary. We identified, thematized, and discussed key issues of ethical salience. Results: Eight areas of ethical salience for outcome prioritization emerged: 1) Public health and distributive justice, 2) Scarcity of resources, 3) Heterogeneity and changing circumstances, 4) Knowledge of treatment, 5) Values and circumstances, 6) Conflicting priorities, 7) Communication, autonomy and caregiver issues, and 8) Disclosure of risk. Conclusion: These areas highlight the difficult balance to be struck when allocating resources, when measuring and prioritizing outcomes, and when individual preferences are sought. We conclude by reflecting on how tools in social sciences and ethics can help address challenges posed by resource allocation, measuring and prioritizing outcomes, and eliciting stakeholder preferences. Show more

Keywords: Alzheimer’s disease, dementia, ethics, health priorities

DOI: 10.3233/JAD-191300

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Tomoto, Tsubasa | Tarumi, Takashi | Chen, Jason | Pasha, Evan P. | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Background: Cerebral blood flow (CBF) is sensitive to changes in arterial CO2 , referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear. Objective: To determine whether CVMR is altered in aMCI and is associated with cognitive performance. Methods: Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2 ) with capnography during hypocapnia (hyperventilation) …and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS). Results: At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p  < 0.05). Logical Memory recall scores were positively correlated with hypocapnia (r  = 0.283, r  = 0.322, p  < 0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r  = –0.347, r  = –0.446, p  < 0.01). Similar correlations were observed in D-KEFS Trail Making scores. Conclusion: Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD. Show more

Keywords: Cerebral blood flow, cerebral vasomotor reactivity, hypercapnia, hypocapnia, mild cognitive impairment, transcranial Doppler

DOI: 10.3233/JAD-200194

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Palacios, Natalia | Lee, Jong Soo | Scott, Tammy | Kelly, Rachel S. | Bhupathiraju, Shilpa N. | Bigornia, Sherman J. | Tucker, Katherine L.

Article Type: Research Article

Abstract: Background: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer’s disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. Objective: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. Methods: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, …apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. Results: Of 621 metabolites, FDR corrected (p  < 0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, β-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function. Conclusion: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults. Show more

Keywords: Cognitive function, diabetes, Puerto Ricans, metabolomics

DOI: 10.3233/JAD-200040

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Breuza, Lionel | Arighi, Cecilia N. | Argoud-Puy, Ghislaine | Casals-Casas, Cristina | Estreicher, Anne | Famiglietti, Maria Livia | Georghiou, George | Gos, Arnaud | Gruaz-Gumowski, Nadine | Hinz, Ursula | Hyka-Nouspikel, Nevila | Kramarz, Barbara | Lovering, Ruth C. | Lussi, Yvonne | Magrane, Michele | Masson, Patrick | Perfetto, Livia | Poux, Sylvain | Rodriguez-Lopez, Milagros | Stoeckert, Christian | Sundaram, Shyamala | Wang, Li-San | Wu, Elizabeth | Orchard, Sandra | IMEx Consortium, UniProt Consortium

Article Type: Research Article

Abstract: Background: The analysis and interpretation of data generated from patient-derived clinical samples relies on access to high-quality bioinformatics resources. These are maintained and updated by expert curators extracting knowledge from unstructured biological data described in free-text journal articles and converting this into more structured, computationally-accessible forms. This enables analyses such as functional enrichment of sets of genes/proteins using the Gene Ontology, and makes the searching of data more productive by managing issues such as gene/protein name synonyms, identifier mapping, and data quality. Objective: To undertake a coordinated annotation update of key public-domain resources to better support Alzheimer’s disease …research. Methods: We have systematically identified target proteins critical to disease process, in part by accessing informed input from the clinical research community. Results: Data from 954 papers has been added to the UniProtKB, Gene Ontology, and the International Molecular Exchange Consortium (IMEx) databases, with 299 human proteins and 279 orthologs updated in UniProtKB. 7,45 binary interactions were added to the IMEx human molecular interaction dataset. Conclusion: This represents a significant enhancement in the expert curated data pertinent to Alzheimer’s disease available in a number of biomedical databases. Relevant protein entries have been updated in UniProtKB and concomitantly in the Gene Ontology. Molecular interaction networks have been significantly extended in the IMEx Consortium dataset and a set of reference protein complexes created. All the resources described are open-source and freely available to the research community and we provide examples of how these data could be exploited by researchers. Show more

Keywords: Alzheimer’s disease, Cytoscape network analysis, data curation, database, neurobiology, protein

DOI: 10.3233/JAD-200206

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Vidoni, Eric D. | Kamat, Ashwini | Gahan, William P. | Ourso, Victoria | Woodard, Kaylee | Kerwin, Diana R. | Binder, Ellen F. | Burns, Jeffrey M. | Cullum, Munro | Hynan, Linda S. | Vongpatanasin, Wanpen | Zhu, David C. | Zhang, Rong | Keller, Jeffrey N.

Article Type: Research Article

Abstract: Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined …as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n  = 407). Sites differed in their prevalence of polypharmacy, χ 2 (3) = 56.0, p  < 0.001. A nearly identical percentage of the 2,077 prescribed (51.8%) and over the counter (48.2%) medications were present in the overall medication profile. The presence of diabetes (87.5%), hyperlipidemia (88.2%), or both (97.7%) was associated with a higher prevalence of polypharmacy than participants who exhibited hypertension in the absence of either of these conditions (63.2%), χ 2 (3) = 35.8, p  < 0.001. Conclusion: Participants in a dementia risk study had high levels of polypharmacy, with the co-existence of diabetes or hyperlipidemia associated with a greater prevalence of polypharmacy as compared to having hypertension alone. Show more

Keywords: Alzheimer’s disease, dementia, hypertension, inappropriate medication, polypharmacy, risk factor

DOI: 10.3233/JAD-200122

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Gárate-Vélez, Lorena | Escudero-Lourdes, Claudia | Salado-Leza, Daniela | González-Sánchez, Armando | Alvarado-Morales, Ildemar | Bahena, Daniel | Labrada-Delgado, Gladis Judith | Rodríguez-López, José Luis

Article Type: Research Article

Abstract: Background: Iron nanoparticles, mainly in magnetite phase (Fe3 O4 NPs), are released to the environment in areas with high traffic density and braking frequency.Fe3 O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3 O4 NPs on primary rat brain microvascular endothelial …cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3 O4 NPs that mimic the environmental ones (miFe3 O4 ) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3 O4 NPs, with a mean diameter of 8.45±0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3 O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3 O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3 O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage. Show more

Keywords: Blood-brain barrier, cytotoxicity, in vitro , magnetite nanoparticles

DOI: 10.3233/JAD-190929

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Sheng, Can | Sun, Yu | Wang, Min | Wang, Xiaoni | Liu, Yi | Pang, Dongqing | Liu, Jiaqi | Bi, Xiaoxia | Du, Wenying | Zhao, Mingyan | Li, Yuxia | Li, Xiaobo | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Visual rating scales for medial temporal lobe atrophy (MTA) and posterior atrophy (PA) have been reported to be useful for Alzheimer’s disease diagnosis in routine clinical practice. Objective: To investigate the efficacy of combined MTA and PA visual rating scales to discriminate amnestic mild cognitive impairment (aMCI) patients from healthy controls. Methods: This study included T1-weighted MRI images from two different cohorts. In the first cohort, we recruited 73 patients with aMCI and 48 group-matched cognitively normal controls for training and validation. Visual assessments of MTA and PA were carried out for each participant. Global …gray matter volume and density were estimated using voxel-based morphometry analysis as the objective reference. We investigated the discriminative power of a single visual rating scale and the combination of the MTA and PA rating scales for identifying aMCI. The second cohort, consisting of 33 aMCI patients and 45 controls, was used to verify the reliability of the visual assessments. Results: Compared with the single visual rating scale, the combination of the MTA and PA exhibited the best discriminative power, with an AUC of 0.818±0.041, which was similar to the diagnostic accuracy of the gray matter volumetric measures. The discriminative power of the combined MTA and PA was verified in the second cohort (AUC 0.824±0.058). Conclusion: The combined MTA and PA rating scales demonstrated practical diagnostic value for distinguishing aMCI patients from controls, suggesting its potential to serve as a convenient and reproducible method to assess the degree of atrophy in clinical settings. Show more

Keywords: Magnetic resonance imaging, medial temporal lobe atrophy, mild cognitive impairment, posterior atrophy, visual rating scales

DOI: 10.3233/JAD-200016

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Lombardi, Gemma | Pupi, Alberto | Bessi, Valentina | Polito, Cristina | Padiglioni, Sonia | Ferrari, Camilla | Lucidi, Giulia | Berti, Valentina | De Cristofaro, Maria Teresa | Piaceri, Irene | Bagnoli, Silvia | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Research Article

Abstract: Background: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. Objectives: 1) To verify that cerebrospinal fluid (CSF) Aβ42 /Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42 ; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. Method: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein …E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. Results: CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen’s K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET–). FDG-PET and all CSF markers (Aβ42 , AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion: 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET–discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, diagnosis, PET scan

DOI: 10.3233/JAD-200119

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Luiu, Anna Laura | Favez, Nicolas | Betrancourt, Mireille | Szilas, Nicolas | Ehrler, Frederic

Article Type: Research Article

Abstract: Background: Family caregivers of people with Alzheimer’s disease are the most important support in concrete personal and economic terms. Family dynamics play a fundamental role in the provision of informal caregiving benefits. Objective: This review aims to identify factors related to the family caregiving of relatives with Alzheimer’s disease, taking specifically into account the construct of coping and expressed emotion. Methods: This is a systematic review including articles selected using search terms including “caregivers,” “Alzheimer’s,” “family,” and “relationship” in research databases. Findings were synthesized and categorized into themes. Results: A total of 454 abstracts …were identified. Following screening, lateral searches, and quality appraisal, 36 studies were included for synthesis. A total of 5 themes were identified: burden; demographics; coping strategies; caregiver mental health; and family dynamics and expressed emotions. Conclusion: The quality and level of evidence supporting each theme varied. We need further research into family dynamics ameliorating the caregiving and how to measure it. Show more

Keywords: Alzheimer’s disease, family caregivers, family relationship, systematic review

DOI: 10.3233/JAD-200125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Gao, Yiwen | Zhang, Nan | Lv, Chunmei | Li, Na | Li, Xueqin | Li, Weiwei

Article Type: Research Article

Abstract: Background: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer’s disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. Objective: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. Methods: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro . The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow …cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. Results: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. Conclusion: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , miR-361-3p, resveratrol, SNHG1, ZNF217

DOI: 10.3233/JAD-191303

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Arroyo-Anlló, Eva M. | Sánchez, Jorge Chamorro | Gil, Roger

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) provides a valuable field of research into impairment of self-consciousness (SC), because AD patients have a reduced capacity to understand their mental world, to experience and relive previous personal events, as well as to interpret thoughts, feelings, and beliefs about themselves. Several studies observed that AD patients had an altered SC, but not a complete abolition of it. Emotions are an integral part of the construction of personal identity, therefore of Self. In general, most studies on emotion in AD patients have observed that emotion is not completely abolished and it lets them better remember autobiographical events …with greater emotional charge. The positive effect of autobiographical memories rich in emotional content, evoked directly/automatically by sensorial stimuli such as familiar odors or music, could be used to reestablish/reinforce the permanence and coherence of the Self in AD. We studied the research of empirical evidence supporting the power of the sensorial cues associated with emotion, which could be capable of enhancing the SC in AD. We presented the studies about “Emotional stimulations” using odor, music, or taste cues in AD. All studies have shown to have a positive impact on SC in AD patients such as odor-evoked autobiographical memories, taste/odor-evoked autobiographical memories, emotional sensorial stimulation using musical cues, and multi-sensorial stimulations using healing gardens. We found research supporting the notion that emotional sensorial stimulations can even temporarily exalt memory, affective state, and personal identity, that is, the SC in AD. The emotional sensory stimulations could be used as a tool to activate the SC in AD and hence improve the quality of life of patients and caregivers. Show more

Keywords: Alzheimer’s disease, dementia, emotion, healing garden, music, neurodegenerative disease, non-pharmacological therapy, odor, self-consciousness, sensorial stimulation, smell, taste

DOI: 10.3233/JAD-200408

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Hollinger, Kristen R. | Zhu, Xiaolei | Khoury, Elizabeth S. | Thomas, Ajit G. | Liaw, Kevin | Tallon, Carolyn | Wu, Ying | Prchalova, Eva | Kamiya, Atsushi | Rojas, Camilo | Kannan, Sujatha | Slusher, Barbara S.

Article Type: Research Article

Abstract: Background: Given the emergent aging population, the identification of effective treatments for Alzheimer’s disease (AD) is critical. Objective: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model. Methods: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4–5 months and cognitive performance was assessed using …the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083. Results: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings, postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment. Conclusion: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, APOE, glutamate, glutaminase, microglia

DOI: 10.3233/JAD-190588

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Sharda, Nidhi | Pengo, Thomas | Wang, Zengtao | Kandimalla, Karunya K.

Article Type: Research Article

Abstract: Background: Synaptic dysfunction prevalent in Alzheimer’s disease (AD) brain is closely associated with increased accumulation of amyloid-β (Aβ ) peptides in the brain parenchyma. It is widely believed that Aβ peptides trigger synaptic dysfunction by interfering with the synaptic vesicular fusion and the release of neurotransmitters, primarily facilitated by the SNARE protein complexes formed by VAMP-2, SNAP-25, and syntaxin-1. However, Aβ interactions with SNARE proteins to ultimately disrupt synaptic vesicular fusion are not well understood. Objective: Our objective is to elucidate mechanisms by which Aβ peptides perturb SNARE complexes. Methods: Intensity (qualitative) …and lifetime (quantitative) based measurements involving Forster (fluorescence) resonance energy transfer (FRET) followed by fluorescence lifetime imaging microscopy (FLIM) were employed to investigate the effect of Aβ peptides on dynamic interactions between VAMP-2, labeled with cerulean (Cer) at the N-terminus (FRET donor), and SNAP-25 labeled with citrine (Cit) on the N-terminus (FRET acceptor). The FRET and FLIM interactions at the exocytosis locations on the pre-synaptic membrane were recorded under spontaneous and high potassium evoked conditions. Moreover, cellular accumulation of fluorescein labeled Aβ (F-Aβ ) peptides and their co-localization with Cer-VAMP2 was investigated by confocal microscopy. Results: The F-Aβ 40 and F-Aβ 42 are internalized by differentiated N2A cells, where they colocalize with Cer-VAMP2. Both Aβ 40 and Aβ 42 decrease interactions between the N-termini of Cer-VAMP2 and Cit-SNAP25 in N2A cells, as determined by FRET/FLIM. Conclusion: By perturbing the N-terminal interactions between VAMP-2 and SNAP-25, Aβ 40 and Aβ 42 , can directly interfere with the SNARE complex formation, which is critical for the docking and fusion of synaptic vesicles Show more

Keywords: Amyloid-β peptides, Alzheimer’s disease, exocytosis, FLIM, FRET, SNARESNAP-25, synaptic vesicular fusion, VAMP-2

DOI: 10.3233/JAD-200065

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Xu, Wei | Sun, Fu-Rong | Tan, Chen-Chen | Tan, Lan | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer’s disease (AD), which might be explained by a reverse causal relationship. Objective: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment. Methods: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical …stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function. Results: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A–/TN–and CDR = 0, p  < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p  = 0.023, β = –14). Individuals in amyloid positive group exhibited faster weight loss (time×group interaction p  = 0.019, β = –0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders. Conclusion: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease. Show more

Keywords: Alzheimer’s disease, amyloid, body mass index, longitudinal

DOI: 10.3233/JAD-200524

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Stypa, Vanessa | Häussermann, Peter | Fleiner, Tim | Neumann, Sandra

Article Type: Research Article

Abstract: Background: The Quality of Life–Alzheimer’s Disease (QoL-AD) scale is a widely used measure of quality of life (QoL) in dementia. Although the instrument has been validated in several languages, the psychometric properties of the German self-report version have not yet been analyzed. Objective: This study examines the internal consistency, test-retest reliability, and construct validity of the German QoL-AD self-report scale. Methods: The sample included 30 patients suffering from mild to moderate Alzheimer’s disease or vascular dementia (19 females; mean age 77.3 years; mean Mini-Mental State Examination (MMSE) score 19.7 points). To determine test-retest reliability, the QoL-AD …self-report scale was re-administered four to seven days apart. For construct validity analysis, the Dementia Quality of Life instrument (DQoL), Geriatric Depression Scale (GDS), MMSE, and an adapted short form of the Neuropsychiatric Inventory (NPI) were used. Results: The German QoL-AD self-report scale shows an internal consistency of α = 0.79 and a test-retest reliability of r  = 0.75 (p  < 0.01). Regarding construct validity, there was a significant positive correlation between the total scores of the QoL-AD and DQoL (r  = 0.47, p  < 0.05). The analysis revealed no significant correlations with the GDS or the adapted NPI. No association could be observed between the QoL-AD and the MMSE (r  = 0.01), confirming divergent validity. Conclusion: The results indicate that the German QoL-AD self-report scale is a suitable instrument for assessing QoL in patients suffering from mild to moderate dementia, thus supporting its use in clinical practice and research. Show more

Keywords: Alzheimer’s disease, dementia, Germany, quality of life, reliability and validity, self report

DOI: 10.3233/JAD-200400

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Melgarejo, Jesus D. | Aguirre-Acevedo, Daniel C. | Gaona, Ciro | Chavez, Carlos A. | Calmón, Gustavo E. | Silva, Eglé R. | de Erausquin, Gabriel A. | Gil, Mario | Mena, Luis J. | Terwilliger, Joseph D. | Arboleda, Humberto | Scarmeas, Nikolaos | Lee, Joseph H. | Maestre, Gladys E.

Article Type: Research Article

Abstract: Background: Dementia of the Alzheimer’s type (DAT) impacts Hispanics disproportionately, with almost a twofold elevated risk of developing DAT, as well as earlier onset of the disease, than in non-Hispanic Whites. However, the role of main risk factors for DAT, such as APOE ɛ 4 and blood pressure (BP) levels, remains uncertain among Hispanics. Objective: To investigate the association of APOE ɛ 4 and BP levels, measures with 24 h ambulatory BP monitoring, with incidence of DAT in an elderly cohort of Hispanics. Methods: 1,320 participants from the Maracaibo Aging Study, free of dementia at the …baseline, and with ambulatory BP measurements and APOE genotype available were included. Adjusted Cox proportional models were performed to examine 1) the incidence of DAT and 2) the relationship between BP levels and DAT according to APOE genotypes. Models were adjusted by competing risk of death before the onset of DAT. Model performance was assessed by likelihood test. Results: The average follow-up time was 5.3 years. DAT incidence was 5.8 per 1000 person-year. APOE ɛ 4 carriers had a higher risk of DAT. In unadjusted analyses, conventional, 24 h, and nighttime systolic BP levels were significantly higher in participants who developed DAT and of APOE ɛ 4 carriers (p < 0.05). After adjustment for competing for risk, only higher nighttime systolic BP was associated with DAT incidence, but only among subjects carrying APOE ɛ 4. Conclusion: In this Hispanic population, both APOE ɛ 4 genotype and assessment of nocturnal systolic BP (rather than diurnal or office BP) were necessary to estimate DAT risk. Show more

Keywords: Alzheimer’s disease, ambulatory blood pressure monitoring, Apolipoprotein E, dementia of Alzheimer’s type, Hispanics, night-time blood pressure

DOI: 10.3233/JAD-200430

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Lim, Sahnah | Mohaimin, Sadia | Min, Deborah | Roberts, Timothy | Sohn, Young-Jin | Wong, Jazmine | Sivanesathurai, Ragavan | Kwon, Simona C. | Trinh-Shevrin, Chau

Article Type: Review Article

Abstract: Background: The Asian American, Native Hawaiian, and Pacific Islander (AANHPI) aging population is rapidly growing and the burden of Alzheimer’s disease and its related dementias (ADRD) will likely mirror this demographic growth. AANHPIs face significant barriers in obtaining timely ADRD diagnosis and services; yet little is known about ADRD in this population. Objective: The study objective is to conduct a systematic review on the published literature on ADRD among AANHPIs to identify gaps and priorities to inform future research and action plans. Methods: The systematic review was conducted following the PRISMA Protocol for Systematic Reviews. Co-author …(TR), an experienced Medical Librarian, searched PubMed, EMBASE, PsycINFO, Cochrane Central of Clinical Trials, Ageline, and Web of Science for peer-reviewed articles describing ADRD among AANHPIs. The search was not limited by language or publication date. Each citation was reviewed by two trained independent reviewers. Conflicts were resolved through consensus. Results: The title/abstract and full texts of 1,447 unique articles were screened for inclusion, yielding 168 articles for analysis. Major research topics included prevalence, risk factors, comorbidities, interventions and outreach, knowledge and attitudes, caregiving, and detection tools. A limited number of studies reported on national data, on NHPI communities generally, and on efficacy of interventions targeting AANHPI communities. Conclusion: To our knowledge, this is the first systematic review on ADRD among AANHPI populations. Our review provides a first step in mapping the extant literature on ADRD among this underserved and under-researched population and will serve as a guide for future research, policy, and intervention. Show more

Keywords: Dementia, inequalities, race, review

DOI: 10.3233/JAD-200509

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020