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