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

Article Type: Correction

DOI: 10.3233/JAD-199006

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2019

Authors: Thunell, Johanna | Ferido, Patricia | Zissimopoulos, Julie

Article Type: Short Communication

Abstract: We examined how methods used for identifying dementia in administrative claims affected dementia incidence across racial/ethnic populations using a 100% sample of Medicare beneficiaries (n  = 23,793,452). We found levels differed by method from 3.1% annual incidence to 3.6% in 2014. Dementia incidence declined 2007 to 2014, but choice of method differentially impacted levels and trends by race/ethnicity. Methods using codes for dementia diagnosis and drugs to treat symptoms identified proportionally more Hispanics and Asians with dementia than other race/ethnicities, while codes for dementia diagnosis, drugs, and symptoms identified proportionally more whites and American Indians/Alaska Natives with dementia than other race/ethnicities.

Keywords: Alzheimer’s disease, dementia, diagnosis, incidence, measurement

DOI: 10.3233/JAD-190310

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Šaltytė Benth, Jūratė | Kersten, Hege

Article Type: Correction

DOI: 10.3233/JAD-199007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2019

Authors: Fanning, Laura | Ryan-Atwood, Taliesin E. | Bell, J. Simon | Meretoja, Atte | McNamara, Kevin P. | Dārziņš, Pēteris | Wong, Ian C.K. | Ilomäki, Jenni

Article Type: Correction

DOI: 10.3233/JAD-199005

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Ralbovsky, Nicole M. | Halámková, Lenka | Wall, Kathryn | Anderson-Hanley, Cay | Lednev, Igor K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRDs) are being diagnosed at epidemic rates, with incidence to triple from 35 to 115 million cases worldwide. Most ADRDs are characterized by progressive neurodegeneration, and Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. The ideal moment for diagnosing ADRDs is during the earliest stages of its progression; however, current diagnostic methods are inefficient, expensive, and unsuccessful at making diagnoses during the earliest stages of the disease. Objective: The aim of this project was to utilize Raman hyperspectroscopy in combination with machine learning to develop a …novel method for the diagnosis of AD based on the analysis of saliva. Methods: Raman hyperspectroscopy was used to analyze saliva samples collected from normative, AD, and mild cognitive impairment (MCI) individuals. Genetic Algorithm and Artificial Neural Networks machine learning techniques were applied to the spectral dataset to build a diagnostic algorithm. Results: Internal cross-validation showed 99% accuracy for differentiating the three classes; blind external validation was conducted using an independent dataset to further verify the results, achieving 100% accuracy. Conclusion: Raman hyperspectroscopic analysis of saliva has a remarkable potential for use as a non-invasive, efficient, and accurate method for diagnosing AD. Show more

Keywords: Alzheimer’s disease, artificial neural networks, early diagnosis, genetic algorithm, machine learning, mild cognitive impairment, Raman spectroscopy, saliva

DOI: 10.3233/JAD-190675

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Kumar, Subodh | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: MicroRNA-455-3p (miR-455-3p) is identify as a member of broadly conserved miRNA family expressed in most of the phylum and species. In humans, miR-455 is present on the human chromosome 9 at locus 9q32 and encoded by the human COL27A1 gene (collagen type XXVII alpha 1 chain). The role of miR-455 has been implicated in various human diseases such as cartilage development, adipogenesis, preeclampsia, and cancers, e.g., colon cancer, prostate cancer, hepatocellular carcinoma, renal cancer, oral squamous cancer, skin cancer, and non-small cell lung cancer. Recently, our laboratory discovered the biomarker and therapeutic relevance of miR-455-3p in Alzheimer’s disease (AD). Our …global microarray analysis of serum samples from AD patients, mild cognitive individuals (MCI), and healthy subjects unveiled the high level of miR-455-3p in AD patients relative to MCI and healthy controls. Further, validation analysis using different kinds of AD samples such as serum, postmortem brains, AD fibroblasts, AD B-lymphocytes, AD cell lines, AD mouse models, and AD cerebrospinal fluid confirmed the biomarker potential of miR-455-3p. The mechanistic link of miR-455-3p in AD was determined via modulation of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) levels. Luciferase reporter assay confirmed AβPP as validated target of miR-455-3p. Our study on mouse neuroblastoma cells revealed the protective role of miR-455-3p against Aβ-induced toxicities. We also noticed that miR-455-3p enhances cell survival and lifespan extension. High level of miR-455-3p reduces Aβ toxicity, enhances mitochondrial biogenesis and synaptic activity, and maintains healthy mitochondrial dynamics. Based on these evidences, we cautiously conclude that miR-455-3p is a promising peripheral biomarker and therapeutic candidate for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, microRNA-455-3p

DOI: 10.3233/JAD-190583

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Nebeker, Camille | Leow, Alex D. | Moore, Raeanne C.

Article Type: Review Article

Abstract: The implementation of digital health technologies into research studies for Alzheimer’s disease and other clinical populations is on the rise. Digital tools and strategies create opportunities to further expand the framework for conducting research beyond the traditional medical research model. The combination of participatory and community-based research methods, electronic health records, and the creation of multi-dimensional, large-scale research platforms to support precision medicine, along with the Internet of Things era, have led to more engaged and informed research participants. Research participants increasingly possess an expectation they will play a critical role as partners in the design and conduct of research. …Moreover, there is growing interest among research participants to have access to individual-level research data in real-time and/or at study completion. The traditional medical research model is largely one-directional where participants contribute data that is analyzed by researchers to yield generalizable knowledge. In this Ethics Review, we discuss a framework for a more nuanced intermediate research model, which is largely bidirectional and individually customized. Based on the seven ethical guidelines adopted by the National Institutes of Health, we speak to the ethical challenges of this intermediate type research. We also introduce a concept we are calling “MyTerms,” in which prospective participants tailor the terms and conditions of informed consent to their personalized preferences for receiving information, including research results. Digital health technologies offer a convenient and flexible approach for researchers to develop protocols that make it possible for participants to obtain access to their study data in a personalized and meaningful way. Show more

Keywords: Cognitive dysfunction, digital medicine, disclosure, information dissemination, informed consent, mobile health, patient rights, privacy, research ethics, return of results

DOI: 10.3233/JAD-190589

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Mattos, Meghan K. | Lingler, Jennifer H.

Article Type: Other

Keywords: Data disclosure, data management, data sharing, ecological momentary assessment, ethics, research subjects

DOI: 10.3233/JAD-190725

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2019

Authors: Hashimoto, Masakazu | Yamazaki, Akira | Ohno, Atsushi | Kimura, Toru | Winblad, Bengt | Tjernberg, Lars O.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-β peptide (Aβ) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aβ or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable …blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD. Show more

Keywords: Alzheimer’s disease, APOE, cerebrospinal fluid, diagnosis, mouse, neurodegenerative disease, plasma

DOI: 10.3233/JAD-190700

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Xu, Heng | Yue, Chengjin | Chen, Lin

Article Type: Research Article

Abstract: Many patients with Alzheimer’s disease suffer from severe neuropathic pain. Soluble guanylate cyclase (sGC) is a critical enzyme of the nitric oxide (NO) signaling pathway. Binding of NO to a group of prosthetic heme on sGC initiates the second messenger cGMP synthesis, resulting in increases in the mechanical threshold for neuropathic pain. Nevertheless, the regulation of sGC remains unclear. Here, we aimed to figure out a strategy to reduce sGC levels by microRNA (miRNA) intervention. Bioinformatical studies were then performed to predict sGC-targeting miRNAs; additionally, an assay of dual luciferase reporter was used for evaluating the functional binding of miRNAs …to sGC. Among all sGC-targeting miRNAs, in particularly we found that miR-142-5p markedly inhibited sGC protein translation by pairing to the 3’-UTR of the sGC mRNA. Orthotopic injection of adeno-associated virus carrying miR-142-5p significantly decreased sGC and sGMP levels, resulting in reduction of the neuropathic pain in rats with the left hind leg sciatic nerve injured in the tibia and peroneal branches. In summary, these data show that miR-142-5p induction in injured neurons may be an effective treatment for neuropathic pain and worthy of further investigation as a treatment for those patients with Alzheimer’s disease and neuropathic pain. Show more

Keywords: Alzheimer’s disease, miR-142-5p, neuropathic pain, nitric oxide, soluble guanylate cyclase

DOI: 10.3233/JAD-190743

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Suarez-Gonzalez, Aida | Ocal, Dilek | Pavisic, Ivanna | Peacock, Ashley | Naessens, Michelle | Ahmed, Samrah | Butler, Christopher R. | Leff, Alexander P. | Yong, X.X. | Crutch, Sebastian J.

Article Type: Research Article

Abstract: Background: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. Objective: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). Methods: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) …and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). Results: Reading using ReadClear provided a better subjective reading experience than sham (p  = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p  <  0.0001, r  = 0.82), particularly errors due to omissions (p  = 0.01, r  = 0.50), repeated words (p  = 0.002, r  = 0.69), and regressions in the text (p  = 0.003, r  = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. Conclusion: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users. Show more

Keywords: Assistive technology, dyslexia, posterior cortical atrophy, reading

DOI: 10.3233/JAD-190335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Frison, Eric | Dufouil, Carole | Helmer, Catherine | Berr, Claudine | Auriacombe, Sophie | Chêne, Geneviève

Article Type: Research Article

Abstract: Diabetes is associated with a higher dementia and mortality risk. However, few studies have accounted for death when estimating the association between diabetes and dementia. We estimated absolute and relative risks of all-cause dementia according to diabetes exposure status in older adults while accounting for competing risk of death using illness-death models. Effect modification by specific characteristics (age, gender, education, cardiovascular risk factors, body mass index, cardiovascular history, depressive symptomatology, impaired renal function, and APOE ɛ 4 genotype) was also investigated. We analyzed the Three-City study data, a French population-based cohort of adults aged 65 years and above who …were followed up for 12 years from 1999–2001. Among 8,328 participants selected in the analytical sample (median age, 73.3 years; 60.3% women), 809 (9.3%) presented with diabetes at baseline. Over a median follow-up period of 8.3 years, 836 participants developed incident dementia. Baseline diabetes was associated with a higher risk of dementia: hazard ratio, 1.79 [95% confidence interval, 1.46–2.19]. No effect modification was shown. Diabetes was associated with a higher 12-year absolute risk of dementia and a lower dementia-free life expectancy (e.g., 14.5% [11.2–18.1] versus 8.7% [7.6–10.2], and 13.4 [12.7–14.1] years versus 16.5 [16.0–17.1] years, respectively, for a 70-year-old woman with the highest level of education). These findings support the potential impact of preventing diabetes on reducing dementia risk in older adults, with a 2-3-year higher dementia-free life expectancy for individuals without diabetes, and inform the design of future interventional trials. Show more

Keywords: Cohort studies, death, dementia, type 2 diabetes mellitus

DOI: 10.3233/JAD-190427

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Rouch, Isabelle | Padovan, Catherine | Pongan, Elodie | Boublay, Nawéle | Laurent, Bernard | Dorey, Jean-Michel | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: A link between personality traits and cognitive performances has been shown in normal adults and elderly individuals. Very few studies have evaluated this link in Alzheimer’s disease (AD). Objective: To better understand cognitive performance as regards to personality traits, our study was aimed to evaluate the role of premorbid personality on cognitive functioning in a population of patients presenting prodromal or mild AD. Methods: 181 elderly with prodromal or mild AD participated in a cross-sectional, prospective cohort study. The participants completed a personality inventory and a neuropsychological battery exploring memory, attention, executive function, language, and …praxis. Cognitive performances were compared according to the level of each personality trait, using multivariate MANOVA models. Results: A higher level of neuroticism was associated with lower performances at similarities test (D = 9.49, p  = 0.003), delayed Free and Cued Selective Reminding test (D  = 5.22, p  = 0.02), and digit span score (D = 7.99, p  = 0.006). A higher level of openness was related to better performances at similarities (D = 4.33, p  = 0.04), letter fluency (D = 11.45, p  = 0.001), and category fluency test (D = 5.85, p  = 0.02). Neuroticism interfered negatively with cognitive functioning at the prodromal stage; the association between openness and cognitive function was observed at both prodromal and mild AD stage. Conclusion: These results suggest that personality traits, in particular neuroticism and openness, modulate cognitive abilities in patients with early AD. These results encourage the development of stress management programs to prevent its negative effects on cognitive aging. Show more

Keywords: Alzheimer’s disease, cognitive function, neuroticism, openness, personality

DOI: 10.3233/JAD-190459

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Taheri-Targhi, Somaiyeh | Gjedde, Albert | Araj-Khodaei, Mostafa | Rikhtegar, Reza | Parsian, Zahra | Zarrintan, Sina | Torbati, Mohammadali | Vafaee, Manouchehr Seyedi

Article Type: Review Article

Abstract: According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer’s disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable …mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980–1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia. Show more

Keywords: Alzheimer’s disease, Avicenna, dementia, history of medicine, Persian medicine

DOI: 10.3233/JAD-190345

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Li, Yuxia | Kang, Meimei | Wang, Hongxing | Jin, He | Wang, Xiaozhen | Gan, Wenjing | Zhao, Mingyan | Zhao, Xing | Wang, Rong | Han, Ying

Article Type: Research Article

Abstract: Subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease (AD). Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) has been identified as a biomarker for AD. It was hypothesized that if urinary AD7c-NTP were also elevated in SCD, as it is in prodromal AD (mild cognitive impairment stage), it could be a convenient and efficient clinical biomarker for the early diagnosis of SCD. SCD is often accompanied by a depressive state (DS), and the impact of DS on urinary AD7c-NTP levels remains unknown. A total of 297 right-handed Chinese Han subjects were recruited, including 98 subjects with SCD, 92 patients …with DS, and 107 well-matched cognitively normal controls (NC). The levels of AD7c-NTP in urine samples were measured using an enzyme-linked immunosorbent assay AD7c-NTP kit. Our results demonstrated that urinary AD7c-NTP levels in the SCD group (0.7561±0.5657 ng/mL) were not significantly higher than in either the DS (0.7527±0.5607 ng/mL) or NC (0.7214±0.5077 ng/mL) groups. Furthermore, urinary AD7c-NTP levels were not correlated with Hamilton Depression Rating Scale and Hamilton Anxiety Scale scores, but they were negatively associated with Mini-Mental State Examination scores (r  = –0.222, p  = 0.033) and Montreal Cognitive Assessment-Basic scores (r  = –0.207, p  = 0.048). Urinary AD7c-NTP level is not elevated in SCD and is unaffected by DS. Urinary AD7c-NTP may therefore not be a good potential biomarker for SCD and DS, although it may become elevated with more severe cognitive decline. Show more

Keywords: Alzheimer-associated neuronal thread protein, Alzheimer’s disease, biomarker, depressive state, subjective cognitive decline

DOI: 10.3233/JAD-190401

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Iliadou, Paraskevi | Kladi, Anastasia | Frantzidis, Christos A. | Gilou, Sotiria | Tepelena, Ioanna | Gialaouzidis, Moses | Papaliagkas, Vasileios | Nigdelis, Vasilis | Nday, Christiane M. | Kiosseoglou, Grigorios | Papantoniou, Georgia | Bamidis, Panagiotis D. | Tsolaki, Magda | Moraitou, Despina

Article Type: Research Article

Abstract: Leading theories of affect development and empirical studies suggest that emotion can enhance memory in older adults. Destination memory which is defined as the ability to remember to whom we told a piece of information is being found to be compromised in aging. In the present study, we sought to assess destination memory using emotional stimuli (Emotional Destination Memory, EDM) in 16 older adults with mild cognitive impairment (MCI) and 16 healthy controls and shed light onto its potential neurophysiological aspects. We measured Mu suppression in frontal and temporal regions via EEG in real time while participants performed the task …of EDM. Results showed no group differences in task performance but significant differences in fronto-temporal activations, specifically in electrodes F7 and F8. Differential Mu rhythm pattern was observed between healthy controls and MCI with the first exhibiting Mu suppression and the last Mu enhancement. Furthermore, Mu enhancement in temporal electrodes within the MCI group was associated with lower scores on EDM. The absence of group differences in the task can be explained by the fact that even if there are underlying structural or functional deficits in the MCI group, these deficits are manifested only at neurophysiological level and not at a behavioral level, which is a common pattern in the process of cognitive decline in its initial phases. The overall findings reveal that, even if there are not any behavioral decrements in MCI patients, they show reduced activations in fronto-temporal regions and this can be attributed to general impairment in emotional destination memory due to possible mirror neuron deficiency. Show more

Keywords: Emotional destination memory, fronto-temporal, mild cognitive impairment, mirror neurons, Mu suppression

DOI: 10.3233/JAD-190311

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Ding, Meng-Yuan | Xu, Yi | Wang, Ying-Zhe | Li, Pei-Xi | Mao, Yi-Ting | Yu, Jin-Tai | Cui, Mei | Dong, Qiang

Article Type: Research Article

Abstract: Background: Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors’ quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. Objective: To develop a new clinical risk score for ischemic stroke survivors in predicting 6–12 months PSCI. Methods: We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. …Results: One hundred forty-five subjects completed a 6–12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (β= 0.065, OR = 1.067, 95% CI = 1.016–1.120), years of education (β= –0.346, OR = 0.707, 95% CI = 0.607–0.824), periventricular hyperintensity grading (β= 1.253, OR = 3.501, 95% CI = 1.652–7.417), diabetes mellitus (β= 1.762, OR = 5.825, 95% CI = 2.068–16.412), and the number of acute nonlacunar infarcts (β= 0.569, OR = 1.766, 95% CI = 1.243–2.510) were independently associated with 6–12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832–0.935). Conclusions: The optimized risk model was effective in screening stroke survivors at high risk of developing 6–12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation. Show more

Keywords: Cognitive dysfunction, cohort studies, predictors, stroke

DOI: 10.3233/JAD-190382

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Gallucci, Maurizio | Pallucca, Claudia | Di Battista, Maria Elena | Fougèreand, Bertrand | Grossi, Enzo

Article Type: Research Article

Abstract: Background: Nutrition plays an important role in the aging process. Adherence to the Mediterranean diet (MedDiet) has been shown to be associated with lower rates of diseases. Cognitive status seems to be strongly interrelated with physical well-being, so that one influences the other. Physical performance measures are not only associated with clinical and subclinical age-related modifications, but are also able to predict disability, institutionalization, and mortality. Objective: To evaluate prospectively the associations between Mediterranean-Style Dietary Pattern Score (MSDPS), clinical characteristics, and cognition of the population sample of The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. Methods: …Global cognition, physical performance measures, MSDPS, and other clinical features were detected in 2010 in 82 men and 108 women. These characteristics were evaluated in relation to the physical performance measures identified 3.8 years later in 2013 in the same subjects, using a semantic connectivity map, through Auto-CM system, to grasp further and non-linear associations between variables which might remain, otherwise, undetected. Results: The Auto-CM system’s map shows a close association between better levels of global cognition and MSDPS in 2010 and higher physical performance in 2013. On the other hand, worse levels of global cognition and MSDPS in 2010 are associated with lower physical performance in 2013. Conclusion: The prevention models for successful aging may benefit from integrated programs that include cognitive, physical, and dietary interventions, since these aspects are mutually interrelated. Show more

Keywords: Aging, hand grip, mediterranean-style dietary pattern score, mini-mental state examination, physical performance, short physical performance battery, TRELONG

DOI: 10.3233/JAD-190609

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Gyanwali, Bibek | Shaik, Muhammad Amin | Venketasubramanian, Narayanaswamy | Chen, Christopher | Hilal, Saima

Article Type: Research Article

Keywords: Alzheimer’s disease, cerebral microbleeds, cerebrovascular disease, cognition, mixed-pathology

DOI: 10.3233/JAD-190540

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Lamar, Melissa | León, Adeline | Romo, Karina | Durazo-Arvizu, Ramon A. | Sachdeva, Shruti | Lipton, Richard B. | Perreira, Krista M. | Gallo, Linda C. | Cai, Jianwen | Khambaty, Tasneem | Carrasco, Jessica | Llabre, Maria M. | Eyler, Lisa T. | Daviglus, Martha L. | González, Hector M.

Article Type: Research Article

Abstract: Sixty percent of Hispanics/Latinos are bilingual which research suggests may confer certain cognitive advantages. Female sex confers cognitive advantages in verbal learning and memory compared to male sex, regardless of race or ethnicity. Understanding the independent and interactive associations of bilingualism and sex with cognition may aid in predicting cognitive aging in Hispanics/Latinos. We examined baseline (2008–2011) data from the Hispanic Community Health Study/Study of Latinos, a multicenter, prospective community-based study. Our analyses included 6,110 males and females ≥45 years old who self-reported birth and parents’ origin outside of the continental US, Spanish as their first language, and were evaluated …in Spanish. Bilingualism was assessed along a Likert scale (1 = only Spanish to 4 = English>Spanish) for language proficiency (reading/spoken) and patterns of use (thinking/socializing). Cognitive testing included verbal learning, memory, fluency, and Digit Symbol Substitution (DSS). Linear regression models adjusted for relevant confounders, the complex survey design, and sampling weights. Participants’ self-reported language proficiency was Spanish better than English, while patterns of use suggested more Spanish than English. Higher language proficiency was associated with higher performance on all cognitive indices while higher patterns of use associated with higher fluency and DSS scores (p -values <  0.01). Female sex was associated with higher performance on all cognitive indices (p -values <  0.05). There were no significant interactions with bilingualism (regardless of metric) by sex on cognition. For Hispanics/Latinos residing in the continental US and reporting birth and parents’ origin elsewhere, bilingualism and female sex have independent cognitive benefits that are important to consider when evaluating cognitive performance. Show more

Keywords: Bilingualism, cognition, Hispanics/Latinos, memory, serial learning, sex differences

DOI: 10.3233/JAD-190019

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Linna, Miika | Vuoti, Sauli | Silander, Katariina | Hörhammer, Iiris | Halminen, Olli | Mikkola, Teija | Koivuranta-Vaara, Päivi | Virta, Lauri J. | Koivusalo, Mirkka | Ylisaukko-oja, Tero

Article Type: Research Article

Abstract: Background: The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer’s disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally. Objective: The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD. Methods: This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. …An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals ≥74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model). Results: Early start of anti-dementia medication (treatment started ≤3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication); HR, 0.51; 95% confidence interval (CI), 0.46–0.57). Dementia was the most common recorded cause of death in both groups. Conclusion: This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death. Show more

Keywords: Alzheimer’s disease, cause of death, cholinesterase inhibitors, dementia, Finland, memantine, registry study, risk of death

DOI: 10.3233/JAD-190288

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Luikku, Antti J. | Hall, Anette | Nerg, Ossi | Koivisto, Anne M. | Hiltunen, Mikko | Helisalmi, Seppo | Herukka, Sanna-Kaisa | Junkkari, Antti | Sutela, Anna | Kojoukhova, Maria | Korhonen, Ville | Mattila, Jussi | Lötjönen, Jyrki | Rummukainen, Jaana | Alafuzoff, Irina | Jääskeläinen, Juha E. | Remes, Anne M. | Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Tuomas | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. Objective: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. Methods: 335 shunted iNPH-patients (median 74 years) were followed until death (n  = 185) or 6/2015 (n  = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance …of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. Results: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). Conclusion: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD. Show more

Keywords: Alzheimer’s disease, computer-assisted diagnosis, normal pressure hydrocephalus, Data and results has been partly presented as an abstract at Hydrocephalus 2017, Kobe, Japan

DOI: 10.3233/JAD-190334

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Guo, Zongjun | Peng, Xing | Li, Hui-Yun | Wang, Yunlai | Qian, Ying | Wang, Zhihong | Ye, Dongqing | Ji, Xiaoyun | Wang, Zhixin | Wang, Yanjiang | Chen, Dongwan | Lei, Hongxing

Article Type: Research Article

Abstract: Immune dysregulation has been observed in the brain and blood of patients with Alzheimer’s disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these …14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients. Show more

Keywords: Alzheimer’s disease, immune dysregulation, peripheral blood, precision medicine

DOI: 10.3233/JAD-190666

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Ledreux, Aurélie | Hkansson, Krister | Carlsson, Roger | Kidane, Mhretab | Columbo, Laura | Terjestam, Yvonne | Ryan, Eliza | Tusch, Erich | Winblad, Bengt | Daffner, Kirk | Granholm, Ann-Charlotte | Mohammed, Abdul Kadir H.

Article Type: Research Article

Abstract: Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with …an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74  = 4.22, p  = 0.044, partial η 2  = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population. Show more

Keywords: Aging, brain-derived neurotrophic factor, cognitive training, mindfulness, physical exercise

DOI: 10.3233/JAD-190756

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Chanteloup, Gäetan | Cordonnier, Marine | Moreno-Ramos, Teresa | Pytel, Vanesa | Matías-Guiu, Jorge | Gobbo, Jessica | Cabrera-Martín, María Nieves | Gómez-Pinedo, Ulises | Garrido, Carmen | Matías-Guiu, Jordi A

Article Type: Research Article

Abstract: We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Keywords: Alzheimer’s disease, biomarkers, exosomes, frontotemporal dementia, PET

DOI: 10.3233/JAD-190545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Yokoyama, Shunichi | Yoshinaga, Takuma | Matsuzaki, Juntaro | Suzuki, Hidekazu

Article Type: Research Article

Abstract: Background: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer’s disease (AD). Objective: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone’s therapeutic ability for AD. Methods: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of …the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Results: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p  = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, – 1.2±0.5; teprenone, 0.2±0.5; p  = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p  = 0.013) but not with severe atrophy (p  = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Conclusion: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. Trial Registration: UMIN ID: UMIN000016843 Show more

Keywords: Alzheimer’s disease, dementia, donepezil, drug repositioning, geranylgeranylacetone

DOI: 10.3233/JAD-190305

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Patra, Kalicharan | Giannisis, Andreas | Edlund, Anna K. | Sando, Sigrid Botne | Lauridsen, Camilla | Berge, Guro | Grøntvedt, Gøril Rolfseng | Bråthen, Geir | White, Linda R. | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: The APOE ɛ 4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ 3 conventionally is considered as ‘risk neutral’ although APOE ɛ 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers, and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers, and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with …either a homozygous APOE ɛ 3 (n  = 31 control subjects, and n  = 14 MCI versus n  = 5 AD patients) or APOE ɛ 4 genotype (n  = 1 control subject, n  = 21 MCI and n  = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ 4-carriers and overall correlated significantly to CSF Aβ42 , p(Thr181)-tau, and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but unrelated to plasma homocysteine levels. Importantly, the APOE ɛ 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p  = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p  = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ 3 subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-II, apolipoprotein E, biomarkers, dementia, dimers

DOI: 10.3233/JAD-190175

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Rudenko, Lauren K. | Wallrabe, Horst | Periasamy, Ammasi | Siller, Karsten H. | Svindrych, Zdenek | Seward, Matthew E. | Best, Merci N. | Bloom, George S.

Article Type: Research Article

Abstract: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not …well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, FRET, tauopathies, tau

DOI: 10.3233/JAD-190226

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Lanham, David | Ali, Sana | Davis, Daniel | Rawle, Mark James

Article Type: Research Article

Abstract: Background: Cardiovascular disease remains the most common cause of death in industrialized countries. The use of beta-blockers is well established as a secondary prevention of myocardial infarction. However, little is known about the benefits of beta-blockers for people living with dementia. Objective: To evaluate the use of beta-blockers in people with dementia who have had a myocardial infarction, in order to identify associations between medication use, mortality, re-infarction and functional decline. Methods: We searched for all studies (randomized trials, observational cohorts) reporting beta-blocker use in populations with both dementia and previous myocardial infarction. Relevant keywords were …used in Medline, Embase, and Web of Science up to October 2018. Titles and abstracts were independently screened by two reviewers. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. PRISMA recommendations were followed throughout. Results: Two observational studies were included, representing 10,992 individuals in a community setting and 129,092 individuals from a hospital record-linkage study. One showed use of beta-blockers reduced all-cause mortality (HR 0.74 (95% CI 0.64– 0.86) alongside evidence for an increased rate of functional decline in individuals aged≥65 with moderate to severe cognitive impairment (OR 1.34 (95% CI 1.11– 1.61)). The second study did not find an association between beta-blocker use and mortality in the population living with dementia. Conclusion: There is insufficient evidence to support use of beta-blockers to persons living with dementia. A single study provides limited evidence that beta-blockers improve survival rates but with associated detrimental effects on functional status in nursing home residents with cognitive impairment. Decisions to continue beta-blockers in persons living with dementia should be made on an individual basis. Show more

Keywords: Beta-blockers, dementia, myocardial infarction, secondary prevention, systematic review

DOI: 10.3233/JAD-190503

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Ezzati, Ali | Zammit, Andrea R. | Harvey, Danielle J. | Habeck, Christian | Hall, Charles B. | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Predicting clinical course of cognitive decline can boost clinical trials’ power and improve our clinical decision-making. Machine learning (ML) algorithms are specifically designed for the purpose of prediction; however. identifying optimal features or algorithms is still a challenge. Objective: To investigate the accuracy of different ML methods and different features to classify cognitively normal (CN) individuals from Alzheimer’s disease (AD) and to predict longitudinal outcome in participants with mild cognitive impairment (MCI). Methods: A total of 1,329 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included: 424 CN, 656 MCI, and 249 AD individuals. …Four feature-sets at baseline (hippocampal volume and volume of 47 cortical and subcortical regions with and without demographics and APOE4 ) and six machine learning methods (decision trees, support vector machines, K-nearest neighbor, ensemble linear discriminant, boosted trees, and random forests) were used to classify participants with normal cognition from participants with AD. Subsequently the model with best classification performance was used for predicting clinical outcome of MCI participants. Results: Ensemble linear discriminant models using demographics and all volumetric magnetic resonance imaging measures as feature-set showed the best performance in classification of CN versus AD participants (accuracy = 92.8%, sensitivity = 95.8%, and specificity = 88.3%). Prediction accuracy of future conversion from MCI to AD for this ensemble linear discriminant at 6, 12, 24, 36, and 48 months was 63.8% (sensitivity = 74.4, specificity = 63.1), 68.9% (sensitivity = 75.9, specificity = 67.8), 74.9% (sensitivity = 71.5, specificity = 76.3), 75.3%, (sensitivity = 65.2, specificity = 79.7), and 77.0% (sensitivity = 59.6, specificity = 86.1), respectively. Conclusions: Machine learning models trained for classification of CN versus AD can improve our prediction ability of MCI conversion to AD. Show more

Keywords: Alzheimer’s disease, classification, early diagnosis, machine learning, magnetic resonance imaging, mild cognitive impairment, predictive analytics

DOI: 10.3233/JAD-190262

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Aguirre, Naiara | Costumero, Víctor | Marin-Marin, Lidón | Escudero, Joaquín | Belloch, Vicente | Parcet, María Antonia | Ávila, César

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been associated with memory impairment due to alterations in the medial temporal lobe (MTL) and the precuneus. Therefore, the goal of this study was to investigate the effects of AD on the brain networks associated with the hippocampus and precuneus during an encoding memory task. 68 mild cognitive impairment patients (MCI), 21 AD patients, and 20 healthy controls (HC) were included. Participants were instructed to memorize landscapes while undergoing fMRI scanning, followed by a recognition test. MCI were followed up clinically for 18 months to track conversion status. Independent component analysis (ICA) was performed to investigate …AD effects on precuneus and MTL networks during memory encoding. Behavioral analyses indicate that HC had a better performance than MCI converters (MCIc) and AD. ICA showed that MCIc had significantly higher activation in the MTL-associated network than MCI non converters (MCIn) and AD, including bilateral hippocampus, parahippocampus, and fusiform gyrus. Furthermore, the precuneus-associated network fitted the default mode network, showing a negative correlation with behavioral performance. These findings indicate that the hyperactivation of the hippocampal network displayed by MCIc has potential discrimination capacity to distinguish them of MCIn, and could be interpreted as a compensatory mechanism. Show more

Keywords: Alzheimer’s disease, hippocampus, independent component analysis, memory, precuneus

DOI: 10.3233/JAD-190421

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Smith, Patrick J. | Mabe, Stephanie | Sherwood, Andrew | Babyak, Michael A. | Doraiswamy, P. Murali | Welsh-Bohmer, Kathleen A. | Kraus, William | Burke, James | Hinderliter, Alan | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. Objective: To examine metabolic mechanisms underlying the association between obesity and neurocognition. Methods: We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model …assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. Results: Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p  = 0.043), CRP (p  < 0.001), and leptin (p  < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (β= –0.16, p  = 0.024) and Verbal Memory (β= –0.16, p  = 0.030), but not Visual Memory (β= 0.05, p  = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (β= –0.12, p  = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function. Conclusions: In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance. Show more

Keywords: Cognitive function, executive function, inflammation, insulin sensitivity, leptin, metabolic function, obesity

DOI: 10.3233/JAD-190569

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elmaleh, David R. | Farlow, Martin R. | Conti, Peter S. | Tompkins, Ronald G. | Kundakovic, Ljiljana | Tanzi, Rudolph E.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that …aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, clinical trial design, combined modality therapy, inflammation, selection of subjects, tau protein, treatment outcomes

DOI: 10.3233/JAD-190507

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Moss, Donald E.

Article Type: Article Commentary

Abstract: The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer’s disease patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer’s …disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer’s disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer’s disease, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer’s disease are explored and improved treatment options are suggested. Show more

Keywords: Alzheimer’s disease, anticholinergic, antimuscarinic, brain atrophy, cholinesterase inhibition, cognition, dementia, nerve growth factor, solifenacin, trospium

DOI: 10.3233/JAD-190626

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Pyun, Jung-Min | Kang, Min Ju | Youn, Young Chul | Park, Young Ho | Kim, Sang Yun

Article Type: Research Article

Abstract: Background: Although dementia with Lewy bodies (DLB) is a degenerative disease involving irreversible pathological changes and subsequent progressive cognitive decline, some patients have presented with improved cognitive function at follow-ups. Their clinical and neuropsychological characteristics and the factors influencing this improvement remain unclear. Objective: To investigate differences in clinical and neuropsychological characteristics between DLB patients with and without cognitive improvement at a one-year follow-up, and to identify predictive factors of cognitive improvement. Methods: This retrospective study included 60 DLB patients, 28 patients in the improved group, and 32 patients in the non-improved group. A multiple linear …regression model was used to compare changes in cognitive function test scores between groups over the course of one year. Binary logistic regression analysis was performed to determine the odds ratios (ORs) of depressive symptoms as a predictor for cognitive improvement. Results: The improved group showed significant increases in immediate and delayed verbal memory function in one year over the non-improved group. We also found that baseline depressive symptoms were associated with an increased probability of cognitive improvement (OR 1.234, CI 1.043– 1.460). Conclusion: Depressive symptoms at baseline were related to a higher probability of a cognitive improvement at one-year follow-up. In addition, immediate and delayed verbal memory function showed significant improvement during one year in improved patients compared to non-improved patients. Show more

Keywords: Cognitive improvement, dementia with Lewy bodies, depressive symptoms

DOI: 10.3233/JAD-190685

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Shaffer, Rachel M. | Sheppard, Lianne | Peskind, Elaine R. | Zhang, Jing | Adar, Sara D. | Li, Ge

Article Type: Research Article

Abstract: Background: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5 ) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF). Objective: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer’s disease (AD) individuals. Methods: We collected CSF from 133 community volunteers at VA Puget Sound …between 2001–2012. We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively. Results: Among cognitively normal individuals, a 5μ g/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5μ g/m3 increase in 1-year average PM2.5 , but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals. Conclusions: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, cellular adhesion molecules, cerebrospinal fluid, cerebrovascular disorders, dementia, particulate matter

DOI: 10.3233/JAD-190563

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Charil, Arnaud | Shcherbinin, Sergey | Southekal, Sudeepti | Devous, Michael D. | Mintun, Mark | Murray, Melissa E. | Miller, Bradley B. | Schwarz, Adam J.

Article Type: Research Article

Abstract: At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo …could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo . 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes. Show more

Keywords: Hippocampal sparing, limbic predominant, subtype, tau

DOI: 10.3233/JAD-190264

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Schlegel, Petr | Novotny, Michal | Klimova, Blanka | Valis, Martin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. Therefore, researchers also look for the alternative approaches to its treatment. It is suggested that changes in human gut microbiome mediated by exercise could influence the development and progression of AD and a new term “muscle-gut-brain axis” is introduced. There is much evidence to support this assumption. The gut microbiology is closely related to a wide range of diseases of the nervous system and therefore any negative qualitative and quantitative changes in the composition of the gut microbiota can potentially contribute …to the pathophysiology of AD. Research shows that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics can prevent or alleviate the symptoms of these chronic neurological diseases. Studies also point to the positive effects of movement on the health of seniors. A positive correlation can be found between cognitive functions and physical stress, both in the elderly and in AD patients. Even short-term interventions with a relatively low frequency seem to produce positive results, while physical activities can be performed by using relatively simple and cost-effective means. In addition, physical activity can significantly modulate gut microbiome. Thus, it can be concluded that physical activity in humans seems to correlate with gut microbiome, which can prevent the incidence and development of AD. Show more

Keywords: Alzheimer’s disease, cognitive disorders, dementia, exercise, microbiome, physical activity, probiotics

DOI: 10.3233/JAD-190460

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Moazzami, Kasra | Wittbrodt, Matthew T. | Lima, Bruno B. | Kim, Jeong Hwan | Hammadah, Muhammad | Ko, Yi-An | Obideen, Malik | Abdelhadi, Naser | Kaseer, Belal | Gafeer, M. Mazen | Nye, Jonathon A. | Shah, Amit J. | Ward, Laura | Raggi, Paolo | Waller, Edmund K. | Bremner, J. Douglas | Quyyumi, Arshed A. | Vaccarino, Viola

Article Type: Research Article

Abstract: Background: Circulating progenitor cells (CPC) have been shown to be associated with memory function in healthy adults. However, the relationship between CPCs and memory function in patients with coronary artery disease (CAD) has not been assessed. Objective: To assess the association between CPCs and memory performance among subjects with CAD. Methods: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler Memory Scale-IV and the Trail Making Test Parts A and B. CPCs were enumerated with flow cytometry as CD45med /CD34+ blood mononuclear cells, those co-expressing other …epitopes representing populations enriched for hematopoietic and endothelial progenitors. Results: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all <0.05). There was a significant interaction in the magnitude of this association with race, such that the association of verbal memory scores endothelial progenitor subsets was present in Black but not in White participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making tests. Conclusion: Lower numbers of circulating endothelial progenitor cells are associated with poorer memory function in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Verbal memory function was more strongly associated with CPC counts in Blacks compared to whites with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study. Show more

Keywords: Black, circulating progenitor cell, coronary artery disease, memory

DOI: 10.3233/JAD-190217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Tadokoro, Koh | Morihara, Ryuta | Ohta, Yasuyuki | Hishikawa, Nozomi | Kawano, Satoko | Sasaki, Ryo | Matsumoto, Namiko | Nomura, Emi | Nakano, Yumiko | Takahashi, Yoshiaki | Takemoto, Mami | Yamashita, Toru | Ueno, Setsuko | Wakutani, Yosuke | Takao, Yoshiki | Morimoto, Nobutoshi | Kutoku, Yumiko | Sunada, Yoshihide | Taomoto, Katsushi | Manabe, Yasuhiro | Deguchi, Kentaro | Higashi, Yasuto | Inufusa, Haruhiko | You, Fukka | Yoshikawa, Toshikazu | von Greiffenclau, Markus Matuschka | Abe, Koji

Article Type: Research Article

Abstract: Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer’s disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. …Seventy-eight subjects with MCI were randomized into placebo (n  = 37) and TwX (n  = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p  = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p  = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI. Show more

Keywords: Dementia, dietary supplement, mild cognitive impairment, oxidative stress, randomized controlled trial

DOI: 10.3233/JAD-190644

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Puthusseryppady, Vaisakh | Coughlan, Gillian | Patel, Martyn | Hornberger, Michael

Article Type: Research Article

Abstract: Background: Dementia-related missing incidents are highly prevalent but still poorly understood. This is particularly true for environmental/geospatial risk factors, which might contribute to these missing incidents. Objective: The study aimed to conduct a retrospective, observational analysis on a large sample of missing dementia patient case records provided by the police (n  = 210), covering dates from January 2014 to December 2017. In particular, we wanted to explore 1) whether there were any hotspot regions of missing incidents and 2) the relationship between outdoor landmark density and missing incidents. Methods: Global spatial autocorrelation (Moran’s I) was used to …identify the potential hotspot regions for missing incidents. Meanwhile, spatial buffer and regression modelling were used to determine the relationship between outdoor landmark density and missing incidents. Results: Our demographics measures replicated and extended previous studies of dementia-related missing incidents. Meanwhile, no hotspot regions for missing incidents were identified, while higher outdoor landmark density leads to increased missing incidents. Conclusion: Our results highlight that missing incidents do not occur in isolated hotspots of regions but instead are endemic in patients regardless of location. Higher outdoor landmark density emerges as a significant geospatial factor for missing incidents in dementia, which crucially informs future safeguarding/intervention studies. Show more

Keywords: Dementia, risk factors, spatial navigation, spatial analysis

DOI: 10.3233/JAD-190244

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: André, Perrine | Samieri, Cécilia | Buisson, Charline | Dartigues, Jean-François | Helmer, Catherine | Laugerette, Fabienne | Féart, Catherine

Article Type: Research Article

Abstract: Background: Identifying the mechanisms involved in the pathogenesis of Alzheimer’s disease (AD) remains crucially important. Chronic age-related low-grade inflammation is considered to be one such mechanism, although its causes are unclear. Lipopolysaccharide (LPS)-type endotoxins, a major component of the outer membrane of Gram-negative bacteria, are known as potent pro-inflammatory molecules. Therefore, we hypothesized that greater exposure to circulating LPS, potentially mediated by the inflammatory pathway, would be a key step of the onset of AD. Objective: The aim of this study was to investigate the link between plasma endotoxin-exposure, inflammation, and AD. Methods: Applying a nested …case-control design, we evaluated the associations among baseline plasma endotoxin-exposure (assessed by measuring LPS-binding protein (LBP) and soluble cluster of differentiation-14 (sCD14) levels), inflammation (assessed by measuring interleukin-6 (IL6) levels), and the odds of developing AD over 12 years. Selected from a population-based cohort, 212 incident cases of AD were matched with 424 controls without dementia with regard to age, gender, and education level. Results: After adjusting for a large set of confounders, including the use of anti-inflammatory drugs, only higher LBP levels were significantly associated with a 30% higher odds ratio of developing AD over 12 years (OR 1.30, 95% CIs [1.07–1.59]), regardless of IL6 levels. Conclusion: This large case-control study provides preliminary results concerning plasma endotoxin-exposure among the elderly and suggests that higher LBP levels, an acute-phase reactant involved in the pro-inflammatory response to LPS, are associated with higher odds of developing AD. Show more

Keywords: Alzheimer’s disease, dementia, endotoxins, inflammation, interleukin-6, lipopolysaccharide, lipopolysaccharide-binding protein, soluble cluster of differentiation-14

DOI: 10.3233/JAD-190295

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Oudin, Anna | Andersson, John | Sundström, Anna | Nordin Adolfsson, Annelie | Oudin Åström, Daniel | Adolfsson, Rolf | Forsberg, Bertil | Nordin, Maria

Article Type: Research Article

Abstract: It is widely known that the apolipoprotein E (APOE ) ɛ 4 allele imposes a higher risk for Alzheimer’s disease (AD). Recent evidence suggests that exposure to air pollution is also a risk factor for AD, and results from a few studies indicate that the effect of air pollution on cognitive function and dementia is stronger in APOE ɛ 4 carriers than in non-carriers. Air pollution and interaction with APOE ɛ 4 on AD risk thus merits further attention. We studied dementia incidence over a 15-year period from the longitudinal Betula study in Northern Sweden. As a marker …for long-term exposure to traffic-related air pollution, we used modelled annual mean nitrogen oxide levels at the residential address of the participants at start of follow-up. Nitrogen oxide correlate well with fine particulate air pollution levels in the study area. We had full data on air pollution, incidence of AD and vascular dementia (VaD), APOE ɛ 4 carrier status, and relevant confounding factors for 1,567 participants. As expected, air pollution was rather clearly associated with dementia incidence. However, there was no evidence for a modifying effect by APOE ɛ 4 on the association (p -value for interaction > 0.30 for both total dementia (AD+VaD) and AD). The results from this study do not imply that adverse effects of air pollution on dementia incidence is limited to, or stronger in, APOE ɛ 4 carriers than in the total population. Show more

Keywords: Air pollution, Alzheimer’s disease, apolipoprotein E, dementia

DOI: 10.3233/JAD-181037

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Wiest, Isabella | Wiemers, Tim | Kraus, Max-Joseph | Neeb, Heiko | Strasser, Erwin F. | Hausner, Lucrezia | Frölich, Lutz | Bugert, Peter

Article Type: Research Article

Abstract: Background: Early diagnosis of Alzheimer’s disease (AD) is challenging, and easily accessible biomarkers are an unmet need. Blood platelets frequently serve as peripheral model for studying AD pathogenesis and might represent a reasonable biomarker source. Objective: In the present study, we investigated the potential to differentiate AD patients from healthy controls (HC) based on blood count, platelet morphology, and function as well as molecular markers at the time of first clinical diagnosis. Methods: Blood samples from 40 AD patients and 29 age-matched HC were included for determination of 78 parameter by blood counting, platelet morphometry, aggregometry, …flow cytometry (CD62P, CD63, activated fibrinogen receptor), protein quantification of nicotinic acetylcholine receptor α 7 (nAChRα 7) and caveolin-1 (CAV-1), and miRNA quantification (miR-26b, miR-199a, miR-335). Group comparison between patients and controls was performed in univariate and multivariate statistical analyses. Results: AD patients showed significantly lower aggregation response to ADP and arachidonic acid and significantly decreased CD62P and CD63 surface expression induced by ADP and U46619 compared to HC. Relative nAChRα 7 and CAV-1 expression was significantly higher AD platelets than in HC. Multivariate analysis of 63 parameter revealed significant differences between AD patients and healthy controls. The best performing feature model revealed a sensitivity of 96.6%, a specificity of 80.0%, and a positive predictive value of 89.3%. No grouping could be achieved by using single parameter groups. Conclusion: Significant differences between platelet characteristics from AD patients and HC at the time of first clinical diagnosis were observed. The best performing parameter can be used as a blood-based biomarker for AD diagnosis in a multivariate model in addition to the standardized mental tests. Show more

Keywords: Aggregometry, Alzheimer’s disease, blood-based biomarker, platelet morphology

DOI: 10.3233/JAD-190574

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Montero-Odasso, Manuel | Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-190790

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Huseby, Carol J. | Hoffman, Claire N. | Cooper, Grace L. | Cocuron, Jean-Christophe | Alonso, Ana P. | Thomas, Stefani N. | Yang, Austin J. | Kuret, Jeff

Article Type: Research Article

Abstract: Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer’s disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro . However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography–tandem mass spectrometry approaches and human-derived tau samples. Results …revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation. Show more

Keywords: Aging, Alzheimer’s disease, mass spectrometry, methylation, phosphorylation, post-translational modification, tau protein

DOI: 10.3233/JAD-190604

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Petersen, Maria Skaalum | Restorff, Marjun | Stórá, Tórmóður | Waldemar, Gunhild | Joensen, Sofus

Article Type: Research Article

Abstract: Background: Dementia has become an important public health, economic, and social issue. Knowledge about prevalence, incidence, and trends of dementia in a country is of crucial importance. However, no studies of prevalence or incidence of dementia have been undertaken in the Faroe Islands. Objectives: The aim was to estimate the overall and trend in incidence and prevalence of dementia among individuals ≥60 years in the Faroe Islands from 2010-2017. Methods: Population-based register study where all individuals ≥60 years with a dementia diagnosis from January 2010 to December 2017 were identified. The overall crude and age-and-sex-specific prevalence …and incidence was assessed. Results: The overall crude incidence among individuals ≥60 years from 2010 to 2017 was 5.1 per 1000 individuals and the prevalence 22.5 per 1000 individuals. The age-and sex-standardized annual incidence of dementia fluctuated between 4.8 and 6.7 per 1000, with no clear secular trend while the age-and sex-standardized prevalence increased steadily from 14.5 in 2010 to 30.8 per 1000 individuals in 2017. Conclusion: The age-standardized prevalence and incidence estimates in the Faroes seem to be lower than in other countries. The incidence was relatively stable in the period while the prevalence of dementia simultaneously increased. Show more

Keywords: Dementia, Faroe Islands, incidence study, nationwide study, prevalence study, trend in prevalence and incidence

DOI: 10.3233/JAD-190341

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Bangen, Katherine J. | Armstrong, Nicole M. | Au, Rhoda | Gross, Alden L.

Article Type: Research Article

Abstract: Metabolic syndrome (MetS) has been linked to increased risk of developing cognitive impairment and dementia including Alzheimer’s disease. It remains unclear whether and at what stage in the adult lifespan MetS and its components begin to alter the trajectory of cognitive performance. In the present study, 2,892 Framingham Offspring participants completed health assessments every four years since 1971 and underwent repeat neuropsychological testing from 1999 to 2014. We estimated the associations of levels and changes in cognitive trajectories with hazard of MetS using a joint growth/survival model. All models were adjusted for baseline age, sex, education, and smoking status. Findings …showed that both mid-life and late-life MetS were associated with lower level of cognitive functioning but not cognitive trajectories. Associations were strongest among those who were nondemented and apolipoprotein (APOE ) ɛ 4 noncarriers. In addition, individuals with the most rapid cognitive decline were more likely to have MetS. The pattern of results showed that associations between MetS and cognition varied, depending upon whether the sample was stratified by genetic and cognitive status and whether we considered cognitive performance as a continuous variable or examined categorical groupings. Given that mid-life MetS was associated with poorer cognition at age 55, cognitive changes may occur early during the MetS process. Our findings suggest that those with MetS are at greater risk of dementia given their lower level of cognitive functioning and also suggest that MetS may be a risk factor for decline in the absence of known risk factors including the APOE ɛ 4 allele. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E, cognition, diabetes, metabolic syndrome, neuropsychology, vascular risk

DOI: 10.3233/JAD-190261

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Krishtal, Jekaterina | Metsla, Kristel | Bragina, Olga | Tõugu, Vello | Palumaa, Peep

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder being the major form of dementia worldwide. AD pathology is initiated by cerebral aggregation of amyloid-β (Aβ) peptides in the form of amyloid plaques; however, the mechanism how Aβ peptide aggregates participate in the disease progression and neurodegeneration is still under debate. Human neuroblastoma cell line SH-SY5Y is a convenient cellular model, which is widely used in biochemical and toxicological studies of neurodegenerative diseases. This model can be further improved by differentiation of the cells toward more neuron-like culture using different protocols. In the current study, dbcAMP, retinoic acid with TPA, …or BDNF were used for differentiation of SH-SY5Y cells, and the resulting cultures were tested for the toxicity toward the Aβ42 peptide. The toxicity of Aβ42 peptide depended on the type of differentiated cells: RA and TPA- differentiated cells were most resistant, whereas dbcAMP and RA/BDNF- differentiated cells were more sensitive to Aβ toxicity as compared with non-differentiated cells. The differentiated cultures provide more appropriate cellular models of human origin that can be used for studies of the mechanism of Aβ pathogenesis and for a screening of compounds antagonistic to the toxicity of Aβ peptides. Show more

Keywords: Alzheimer’s disease, amyloid-β , differentiation, SH-SY5Y, toxicity

DOI: 10.3233/JAD-190705

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Sathyan, Sanish | Ayers, Emmeline | Gao, Tina | Milman, Sofiya | Barzilai, Nir | Rockwood, Kenneth | Verghese, Joe

Article Type: Research Article

Abstract: Background: Frailty is highly prevalent among older adults, and associated with cognitive decline. Relationship between frailty and motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by the presence of subjective cognitive complaints and slow gait, is yet to be elucidated. Objective: To examine whether frailty increases the risk of developing incident MCR. Methods: We analyzed 641 adults, aged 65 and above, participating in the LonGenity study. Frailty was defined using a 41-point cumulative deficit frailty index (FI). MCR was diagnosed at baseline and annual follow-up visits using established criteria. Cox proportional hazard models were used …to study the association of baseline frailty with incident MCR, and reported as hazard ratio (HR) with 95% confidence intervals (CI) adjusted for age, sex, and education. Results: At baseline, 70 participants (10·9%) had prevalent MCR. Of the remaining 571 non-MCR participants (mean age 75.0, 57.3% women), 70 developed incident MCR (median follow-up 2.6 years). Higher frailty scores at baseline were associated with an increased risk of incident MCR (HR for each 0.01 increase in the FI: 1.07; 95% CI 1.03–1.11; p  = 0.0002). The result was unchanged even after excluding mobility related or chronic illnesses items from the FI as well as accounting for reverse causation, competing risk of death, baseline cognitive status, social vulnerability, and excluding participants with mild cognitive impairment syndrome. Conclusions: Higher levels of frailty increase risk for developing MCR and suggest shared mechanisms. This association merits further study to identify strategies to prevent cognitive decline. Show more

Keywords: Cognition, cumulative frailty score, dementia, slow gait

DOI: 10.3233/JAD-190517

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Guglielmotto, Michela | Repetto, Ivan Enrico | Monteleone, Debora | Vasciaveo, Valeria | Franchino, Claudio | Rinaldi, Sara | Tabaton, Massimo | Tamagno, Elena

Article Type: Research Article

Abstract:  Neuroinflammation is involved in the pathogenesis of Alzheimer’s disease, and the transcription factor NF-κ B is a player in this event. We found here that the ischemic damage alone or in association with Aβ1-42 activates the NF-κ B pathway, induces an increase of BACE1 and a parallel inhibition of Uch-L1 and TREM2, both in vitro and in vivo , in Tg 5XFAD and in human brains of sporadic AD. This mechanism creates a synergistic loop that fosters inflammation. We also demonstrated a significant protection exerted by the restoration of Uch-L1 activity. The rescue of the enzyme is able …to abolish the decrease of TREM2 and the parameters of neuroinflammation. Show more

Keywords: Alzheimer’s disease, neuroinflammation, NF-kB pathway, stroke, TREM2, Uch-L1

DOI: 10.3233/JAD-190494

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Mayelle, Amandine | El Haj, Mohamad | Antoine, Pascal

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (PwAD) remain able to speak coherently about their daily life for a long time, and their level of awareness could be determined through their discourse. In a grounded-theory approach, awareness of self and awareness of disease are intertwined and can be observed through three domains: mechanisms, objects and modes of expression. Objective: Based on preliminary results, in this article, we present the ASDA (Awareness of Self and Disease Assessment), a new subjective measurement tool for awareness in PwAD. To consider its use in research and practice, we initially performed validation analyses, including internal …consistency, test-retest reliability and interrater reliability analyses. Methods: The new assessment tool consists of a semi-structured interview and ratings of 22 items divided into three categories. As part of our observational study, we assessed a sample of 28 PwAD who participated in four interviews (one every two weeks). Results: The ASDA shows good homogeneity within the domains of awareness and a certain degree of stability between two measurement times and between investigators. Missing values in the results provided information regarding awareness levels within and across the subjects. Conclusion: The results suggest that awareness could be assessed through subjective experience without reference to a comparison. Show more

Keywords: Alzheimer’s disease, anosognosia, awareness, self, self-assessment

DOI: 10.3233/JAD-190371

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Bonfiglio, Viviana | Umegaki, Hiroyuki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: With multimorbidity increasing among older people, polypharmacy and the use of potentially inappropriate medications (PIMs) are assuming a prominent role in the life of the geriatric population. Objective: To investigate the association of polypharmacy and PIM use with a wide range of factors in older people with mild cognitive impairment (MCI) to mild dementia. Methods: The study population comprised 160 outpatients with a Clinical Dementia Rating of 0.5–1 and a Mini-Mental State Examination score of 20–30. Patients were classified as receiving polypharmacy when they took ≥5 different medications at the same time. PIMs were identified …using the STOPP-J criteria. Cognitive, neuropsychological, nutritional, and physical function tests were performed and body measurements taken. Quality of life (QOL) was assessed using both components of the EQ-5D scale, the index score, and the visual analogue scale (QOL VAS). A comorbidity index was calculated for all participants. Results: PIM use was significantly associated with lower scores on the verbal fluency (initial letters) test and QOL index. Participants receiving polypharmacy showed an increased likelihood of worse frailty status and lower QOL VAS score. The number of medications was significantly associated with worse frailty status. Conclusion: In a geriatric population with MCI to mild dementia, PIM use was associated with lower verbal fluency (initial letters) score and lower QOL, while the presence of polypharmacy was correlated with a worse frailty status and lower QOL. The number of medicines, instead, was correlated with a worse frailty status only. Show more

Keywords: Dementia, frailty, polypharmacy, potentially inappropriate medications, quality of life

DOI: 10.3233/JAD-190284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Yang, Alex J.T. | Frendo-Cumbo, Scott | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background: Obesity, insulin resistance, and type 2 diabetes are established risk factors for the development of Alzheimer’s disease (AD). Given this connection, two drugs, metformin (MET) and resveratrol (RESV), are considered for the clearance of amyloid-β peptides through AMPK-mediated activation of autophagy. However, overactivation of AMPK observed in late-stage AD brains and relationships between AMPK and neurogenesis (through mTORC1 inhibition), questions treatment with these drugs. Objective: To examine if MET and/or RESV supplementation activates brain AMPK, regulates markers of autophagy, and affects markers of neuronal health/neurogenesis. Methods: 8-week-old male C57BL/6J mice were fed a low (N = 12; …10% kcal fat; LFD) or high fat diet (N = 40; 60% kcal fat; HFD) for 9 weeks to induce insulin resistance and obesity. HFD mice were then treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks. Hippocampus and prefrontal cortex were extracted for western blotting analysis. Results: Cortex AMPK (T172) and raptor (S792, the regulatory subunit of mTORC1) phosphorylation were upregulated following RESV, COMBO treatments. mTOR (S2448) and ULK1 (S555) activation was seen following MET, COMBO and RESV, COMBO treatments, respectively, in the cortex and hippocampus. p62 content was decreased following RESV, COMBO, with LC3 content being increased following RESV treatment in the cortex. Brain derived neurotropic factor (BDNF) was significantly decreased following RESV, COMBO, and synaptophysin following all treatment in the cortex. Conclusion: These results demonstrate that while treatments upregulated markers of autophagy in the prefrontal cortex, reductions in neuronal health markers question the efficacy of AMPK as a therapy for AD. Show more

Keywords: Autophagy, BDNF, metformin, resveratrol, synaptophysin

DOI: 10.3233/JAD-190123

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Folley, Stephanie | Zhou, Ang | Llewellyn, David J. | Hyppönen, Elina

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE) genotype affects the risk of Alzheimer’s disease (AD) with inconclusive evidence on the opportunity to mitigate related adverse effects by lifestyle changes. Objective: To examine the individual and interactive associations of APOE and objectively-measured physical activity (PA) and sedentary activity with cognitive decline. Methods: We used data from middle-aged and older UK Biobank participants with repeat tests on visuospatial memory (n  = 52,767) and fluid intelligence (n  = 19,713), and who also took part in the accelerometer sub-study. PA and sedentary activity were assessed by a wrist-worn accelerometer over a seven-day period. …Cognitive decline was defined as >1 standard deviation (SD) reduction in memory or fluid intelligence score, and the mean follow up from baseline was 5.8 years. Results: There was an age dependent association between APOE ɛ 4 genotype and memory decline (page-interaction  = 0.01), with the association only seen in participants who were >65 years (OR 1.33, 95% CI 1.11 to 1.24; for <65 years OR 1.06, 95% CI 0.99 to 1.14). The OR for the APOE ɛ 4 association with fluid intelligence decline was 1.11 (95% CI 0.99 to 1.24), and there was no evidence for age interaction (page -interaction  = 0.99). High PA and low sedentary activity were associated with reduced mean memory decline (p  < 0.02 for both). There was no interaction between PA or sedentary activity with APOE ɛ 4 regarding either of the cognitive decline measures (p  > 0.63 for all). Conclusion: This large-scale study using objectively measured PA did not find differential effects of PA on cognitive decline based on APOE genotype. Show more

Keywords: Accelerometry, Apolipoprotein E, APOE, cognitive decline, dementia, gene-environment interaction, physical activity, sedentary, UK Biobank

DOI: 10.3233/JAD-181132

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Javanshiri, Keivan | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Research concerning the potential roles of cardiovascular disease (CaVD) and diabetes mellitus (DM) as risk factors for Lewy body disease (LBD) is limited. These disorders are, however, established risk factors for vascular dementia (VaD) and have been proposed as risk factors for Alzheimer’s disease (AD). Objective: The aim of this study was to investigate the prevalence of CaVD and DM in LBD and compare the results with previous findings in cases with AD, VaD, and mixed AD-VaD (MD). Methods: Autopsy reports at the Clinical Department of Pathology in Lund from 2001–2018 were analyzed. All cases …with a complete neuropathological diagnosis of LBD were selected, not distinguishing between subjects with clinical Parkinson disease dementia and dementia with Lewy bodies, on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through the patients’ medical records and the Swedish National Diabetes Register (NDR) and compared with those of the AD, VaD, and MD cases. Results: In LBD, there was less CaVD, significantly less DM (p  = 0.002) and likewise significantly less hypertension (p  < 0.001) than in VaD. The results of the LBD group were consistent with the results of the AD group. Conclusion: Our findings of a low prevalence of CaVD and CaVD risk factors in LBD and in AD argue against the association between these risk factors and their contribution to the development of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, autopsy, cardiovascular disease, dementia, diabetes mellitus, hypertension, Lewy body disease, risk factors, vascular

DOI: 10.3233/JAD-190485

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Tian, Yuan | Song, Mingrui

Article Type: Research Article

Abstract: Administration of sevoflurane (SEVO) may induce learning and memory deficits, which increases the chances of developing Alzheimer’s disease. Here, we studied the effects of SEVO exposure on rats with a focus on the role of insulin-like growth factor (IGF) signaling. SEVO exposure significantly increased neuron cell apoptosis, and caused poor performance of the rats in behavior tests, by suppressing IGF-1 receptor (IGF1R). Bioinformatic analysis predicted microRNA(miR)-223-3p as an IGF1R-binding miRNA, the level of which increased in neurons after exposure to SEVO. In vitro , miR-223-3p suppressed the translation of IGF1R in neural cells. Moreover, transfection with antisense of miR-223-3p significantly …attenuated SEVO exposure-induced neuron cell apoptosis. Taken together, these data suggest that SEVO-induced miR-223-3p upregulation suppresses IGF1R to impair IGF signaling, which subsequently leads to learning and memory impairments. Show more

Keywords: Alzheimer’s disease, IGF1R, miR-223-3p, sevoflurane

DOI: 10.3233/JAD-190596

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Chatterjee, Pratishtha | Elmi, Mitra | Goozee, Kathryn | Shah, Tejal | Sohrabi, Hamid R. | Dias, Cintia B. | Pedrini, Steve | Shen, Kaikai | Asih, Prita R. | Dave, Preeti | Taddei, Kevin | Vanderstichele, Hugo | Zetterberg, Henrik | Blennow, Kaj | Martins, Ralph N.

Article Type: Research Article

Abstract: Background: Aberrant amyloid-β (Aβ) deposition in the brain occurs two decades prior to the manifestation of Alzheimer’s disease (AD) clinical symptoms and therefore brain Aβ load measured using PET serves as a gold standard biomarker for the early diagnosis of AD. However, the uneconomical nature of PET makes blood markers, that reflect brain Aβ deposition, attractive candidates for investigation as surrogate markers. Objective: Investigation of plasma Aβ as a surrogate marker for brain Aβ deposition in cognitively normal elderly individuals. Methods: Plasma Aβ40 and Aβ42 concentrations were measured using the ultrasensitive Single Molecule Array …(Simoa) assay in 95 cognitively normal elderly individuals, who have all undergone PET to assess brain Aβ deposition. Based on the standard uptake value ratios (SUVR) obtained from PET imaging, using the tracer 18 F-Florbetaben, plasma Aβ was compared between 32 participants assessed to have low brain Aβ load (Aβ–, SUVR <1.35) and 63 assessed to have high brain Aβ load (Aβ+, SUVR ≥1.35). Results: Plasma Aβ42 /Aβ40 ratios were lower in the Aβ+ group compared to the Aβ–group. Plasma Aβ40 and Aβ42 levels were not significantly different between Aβ–and Aβ+ groups, although a trend of higher plasma Aβ40 was observed in the Aβ+ group. Additionally, plasma Aβ42 /Aβ40 ratios along with the known AD risk factors, age and APOE ɛ 4 status, resulted in Aβ+ participants being distinguished from Aβ–participants based on an area under the receiver operating characteristic curve shown to be 78%. Conclusion: Plasma Aβ ratios in this study are a potential biomarker for brain Aβ deposition and therefore, for preclinical AD. However, this method to measure plasma Aβ needs further development to increase the accuracy of this promising AD blood biomarker. Show more

Keywords: Alzheimer’s disease, blood biomarkers, plasma amyloid-β, plasma amyloid-β ratios, preclinical Alzheimer’s disease, single molecule array

DOI: 10.3233/JAD-190533

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Pedrinolla, Anna | Tamburin, Stefano | Brasioli, Anna | Sollima, Alessio | Fonte, Cristina | Muti, Ettore | Smania, Nicola | Schena, Federico | Venturelli, Massimo

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) affect 60–90% of patients with Alzheimer’s disease (AD). Objective: To determine if environmental therapy is an effective strategy to reduce BPSD, we tested 163 patients with AD with Neuropsychiatric Inventory (NPI) before and after 6 months of an indoor therapeutic garden (TG) or standard environment. Methods: A single-blind randomized controlled trial on AD patients with BPSD. Participants were randomized to an indoor TG (N = 82), or standard environment (control, N = 81) for 6 months. Primary outcome: change in the NPI score from baseline (T0) to end of treatment (T1). Secondary …outcomes: change in use of quetiapine, cognition, activities of daily living, salivary cortisol, blood pressure from T0 to T1. Results: NPI score significantly ameliorated (TG versus control: –31.8 points), quetiapine dosage (–150 mg), blood pressure (–2.6 mm Hg), and salivary cortisol (–6.4 to –2.1 Nmol/l) were significantly reduced, the Mini-Mental State Examination significantly improved (1.8 points) in the TG versus control arm at T1 (p  < 0.001). No adverse events were reported. Conclusion: The indoor TG seems safe and may reduce BPSD, medication intake, and cortisol levels in AD. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, cortisol, gardens, non-pharmacological treatment, 0000-0002-1561-2187

DOI: 10.3233/JAD-190394

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Rogojin, Alica | Gorbet, Diana J. | Hawkins, Kara M. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Background: Cognitive-motor integration (CMI) involves concurrent thought and action which requires the interaction of large brain networks. Given that early-stage dementia involves neural network dysfunction, deficits in CMI may prove useful for early dementia detection. Objective: Our research objective was to investigate sex-related differences in the ability to integrate rules into action. Methods: Based on family medical history, we recruited male and female participants both with and without dementia risk factors. Participants did not demonstrate cognitive impairment at the time of testing. Participants were tested on four increasingly dissociated visuomotor tasks (eye and hand movements were …made in different spatial planes and/or visual feedback was reversed) Results: We observed significantly greater hand movement endpoint error scores and corrective path lengths in at-risk females compared to at-risk males in the most complex CMI condition (plane-change + feedback reversal). Multiple regression analyses revealed both sex and family history as significant predictors of worse performance in a CMI condition requiring visual feedback reversal. Further, the regression analyses provided preliminary evidence that having an APOE ɛ 4 allele was a significant predictor of poorer CMI performance in the two plane-change CMI conditions. Conclusion: These data suggest that underlying brain networks controlling simultaneous thought and action may differ between the sexes in ways that may be clinically relevant in dementia progression. Preliminary data also suggest an important connection between APOE variant and CMI performance in individuals at risk of developing dementia. Show more

Keywords: Aging, alzheimer’s disease, apolipoprotein E4, dementia risk, geriatric assessment, motor skills, movement, visuomotor integration

DOI: 10.3233/JAD-190403

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Chandra, Sujyoti | Roy, Avik | Patel, Dhruv R. | Pahan, Kalipada

Article Type: Review Article

Abstract: Mounting evidence has identified that impaired amyloid-β (Aβ) clearance might contribute to Alzheimer’s disease (AD) pathology. The lysosome-autophagy network plays an important role in protein homeostasis and cell health by removing abnormal protein aggregates via intracellular degradation. Therefore, stimulation of cellular degradative machinery for efficient removal of Aβ has emerged as a growing field in AD research. However, mechanisms controlling such pathways and drugs to promote such mechanisms are poorly understood. Aspirin is a widely used drug throughout the world and recent studies have identified a new function of this drug. At low doses, aspirin stimulates lysosomal biogenesis and autophagy …to clear amyloid plaques in an animal model of AD. This review delineates such functions of aspirin and analyzes underlying mechanisms that involve peroxisome proliferator-activated receptor alpha (PPARα )-mediated transcription of transcription factor EB (TFEB), the master regulator of lysosomal biogenesis. Show more

Keywords: Alzheimer’s disease, amyloid plaques, autophagy, lysosomal biogenesis, PPARα, TFEB

DOI: 10.3233/JAD-190586

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Ramasubramanian, Bhagavathi | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: The purpose of our article is to critically assess if TallyHo mice are a true mouse model for type 2 diabetes and Alzheimer’s disease. Diabetes is a lifestyle condition that is characterized by elevated blood glucose due to either insufficient amount of insulin or the body’s inability to use the produced insulin efficiently. Diabetes occurs in multiple forms, including type 1, type 2, type 3, neonatal, and gestational. Type 2 diabetes covers 95% of overall diabetes, found in individuals 65 years of age and above. Both modifiable and non-modifiable factors are involved in developing diabetes. In patients with diabetes, increased …blood glucose levels are reported to induce multiple complications, such as heart disease, stroke, kidney failure, foot ulcers, and damage to the eyes. However, the molecular basis of diabetes is not completely understood. Further, there are no accurate animal model(s) that mimic both type 1 and type 2 diabetes of humans. Multiple polygenic models are being used, including the Goto-Kakizaki rat, the Otzhka Long-Evans Tokushima Fatty rat, the Nagoya Shibata Yasuda mouse, the New Zealand obese mouse, the Tsumura-Suzuki obese diabetes mouse, leptin deficient ob /ob and the leptin receptor deficient db /db mouse models. In 2001, Kim and colleagues described the TallyHo mice that represent many features of type 2 diabetes of humans. Since then, several groups studied TallyHo mice. Only the male mice develop hyperglycemia and the females exhibit features of obesity. Thus, this model can be used to study both diabetes and obesity. The purpose of this article is to discuss recent developments in TallyHo mice research including diabetes onset and progression. Show more

Keywords: Alzheimer’s disease, diabetes, gestational diabetes, modifiable factors, obesity, TallyHo mice

DOI: 10.3233/JAD-190613

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Li, Hui | Luo, Xiao-Bing | Xu, Yan | Hou, Xiao-Yu

Article Type: Research Article

Abstract: Background: Oligomeric amyloid-β peptide (Aβ) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer’s disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric Aβ-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD. Objectives: The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against Aβ neurotoxicity in rat hippocampus. Methods: Oligomeric Aβ25-35 (20 nmol/rat) or …Aβ1-42 (5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after Aβ treatment, respectively. Results: A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after Aβ oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol–40 nmol/rat) suppressed the Aβ-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against Aβ neurotoxicity. Conclusions: Ischemic postconditioning provides neuroprotection against Aβ neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, ischemic postconditioning, NMDA receptors, P38MAPKs

DOI: 10.3233/JAD-190207

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Stirland, Lucy E. | Russ, Tom C. | Ritchie, Craig W. | Muniz-Terrera, Graciela | EPAD Consortium

Article Type: Research Article

Abstract: Background: Multimorbidity (the co-occurrence of multiple chronic conditions) is increasingly common, especially among people with dementia. Few neuroimaging studies have explored amyloid biomarkers in people with multimorbidity. Objective: We aimed to conduct the first study of the association between multimorbidity and cerebrospinal fluid amyloid-β42 (CSF Aβ). Method: The European Prevention of Alzheimer’s Dementia (EPAD) Longitudinal Cohort Study V500.0 dataset includes volunteers aged ≥50 years from 12 sites. Participants undergo detailed phenotyping, including CSF measures and a self-reported medical history. Using logistic and linear regression analyses, we explored the association between multimorbidity and continuous chronic condition …count with CSF Aβ positivity (Aβ42 <1000pg/ml) and continuous CSF Aβ concentration. All models were adjusted for age, sex, APOE status, education, and family history of dementia. Results: Among 447 eligible participants without dementia, the mean (SD) age was 66.6 (6.6) years, 234 (52.3%) were women, and 157 (35.1%) were amyloid positive. With chronic conditions regarded as pseudo-continuous, each additional condition carried a decreased likelihood of amyloid positivity (OR = 0.82, 95% CI: 0.68–0.97; p  = 0.026). With CSF Aβ as a continuous variable, each additional condition was associated with an increase of 54.2 pg/ml (95% CI: 9.9–98.5, p  = 0.017). Having ≥2 conditions was inversely associated with amyloid positivity (OR 0.59, 95% CI: 0.37–0.95, p  = 0.030) compared to one or none. Conclusion: Our findings suggest that the established association between multimorbidity and dementia may be due to a pathway other than amyloid. However, this cross-sectional study does not allow us to make causal inferences. Longitudinal work is required to confirm the inverse association found. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, multimorbidity

DOI: 10.3233/JAD-190222

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Noguchi-Shinohara, Moeko | Hirako, Kohei | Fujiu, Makoto | Sagae, Masahiko | Samuta, Hikaru | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Both cigarette smoking and diabetes mellitus are well-established risk factors for development of dementia. However, the interaction between smoking and diabetes is yet unknown. Objective: In this study, we clarify association between smoking, diabetes, and dementia risk in older adults. Methods: Participants in this study included community residents aged 65 years and older who had participated in a health checkup in 2006, followed for 10 years (n  = 9,403) and had long-term care insurance information data. Furthermore, the risk estimates of smoking status and diabetes diagnosis on dementia adjusted for the competing risk of death prior …to dementia were analyzed. Results: During follow-up, 2,647 participants developed dementia. The smoking status–diabetes interaction on development of dementia was statistically significant (p ≤0.001). Among those patients exposed to both factors, 17% of risk of development of dementia was attributable to the interaction of these factors. Current smokers with diabetes had significantly greater risks of development of dementia than never smokers without diabetes (reference): multivariable-adjusted risk of dementia in current smokers without diabetes (subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.05–1.48); never smokers with diabetes (1.31, 1.16–1.47); and current smokers with diabetes (1.86, 1.39–2.48). However, no such association was noted for former smokers with and without diabetes. Conclusions: Current smoking, but not former smoking, was associated with increased risk of development of dementia in older adults with and without diabetes. Moreover, the synergistic effect of current smoking and diabetes on dementia was noted. Show more

Keywords: Cigarette smoking, dementia, diabetes mellitus, insurance, long-term care

DOI: 10.3233/JAD-190340

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Karayiannis, Christopher | Moran, Chris | Sharman, James E. | Beare, Richard | Quinn, Stephen J. | Phan, Thanh G. | Wood, Amanda G. | Thrift, Amanda G. | Wang, Wei C. | Srikanth, Velandai

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2D) is associated with an increased risk of cognitive impairment and dementia with poorly understood underlying mechanisms. Objective: We examined the role of blood pressure (BP), aortic stiffness, and hemodynamics in this association. Methods: Cross-sectional sample of late middle-aged twins discordant for T2D from the Australian Twin Registry. Measurements included neuropsychological battery and brain MRI including arterial spin labelling (ASL) to measure cerebral perfusion. Mobil-o-Graph devices were used to non-invasively obtain 24-hour BP, aortic stiffness, and hemodynamic measures. Using mixed modelling, we studied associations of T2D with cognition, MRI measures, BP, aortic …stiffness, and hemodynamics. Results: There were 23 twin pairs with mean age 63.7 (SD = 6.1) years. T2D (β=–0.45, p  < 0.001) and age (β=–0.05, p  = 0.022) were independently associated with poorer attention but not with memory or perceptual speed. T2D was associated with reduced nocturnal central systolic BP dipping (β=–3.79, p  = 0.027), but not with BP, aortic stiffness, cerebral perfusion, or other hemodynamic measures. There was a statistically significant interaction between T2D and central systolic BP dipping in predicting attention scores (both p  < 0.05 for the interaction term) whereby there was a positive association between BP dipping and attention scores in those with T2D, but not in those without T2D. Conclusion: We found an association between T2D and reduced nocturnal central systolic dipping, but not with any other measures of BP, stiffness or hemodynamic measures. Further study of the role of nocturnal central BP dipping in the association between T2D and cognitive impairment may help identify potential mechanisms. Show more

Keywords: Blood pressure, cerebrovascular circulation, cognitive dysfunction, dementia, hemodynamics, type 2 diabetes mellitus, vascular stiffness

DOI: 10.3233/JAD-190319

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Flores-Rodríguez, Paola | Harrington, Charles R. | Wischik, Claude M. | Ibarra-Bracamontes, Vanessa | Zarco, Natanael | Navarrete, Araceli | Martínez-Maldonado, Alejandra | Guadarrama-Ortíz, Parménides | Villanueva-Fierro, Ignacio | Ontiveros-Torres, Miguel Angel | Perry, George | Alonso, Alejandra D. | Floran-Garduño, Benjamin | Segovia, José | Luna-Muñoz, José

Article Type: Research Article

Abstract: It has been reported that the main function of tau protein is to stabilize microtubules and promote the movement of organelles through the axon in neurons. In Alzheimer’s disease, tau protein is the major constituent of the paired helical filament, and it undergoes post-translational modifications including hyperphosphorylation and truncation. Whether other functions of tau protein are involved in Alzheimer’s disease is less clear. We used SH-SY5Y human neuroblastoma cells as an in vitro model to further study the functions of tau protein. We detected phosphorylated tau protein as small dense dots in the cell nucleus, which strongly colocalize with …intranuclear speckle structures that were also labelled with an antibody to SC35, a protein involved in nuclear RNA splicing. We have shown further that tau protein, phosphorylated at the sites recognized by pT231, TG-3, and AD2 antibodies, is closely associated with cell division. Different functions may be characteristic of phosphorylation at specific sites. Our findings suggest that the presence of tau protein is involved in separation of sister chromatids in anaphase, and that tau protein also participates in maintaining the integrity of the DNA (pT231, prophase) and chromosomes during cell division (TG-3). Show more

Keywords: Alzheimer’s disease, cell cycle, phospho-tau protein, SC35, SH-SY5Y, staurosporine

DOI: 10.3233/JAD-190155

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Deckers, Kay | Cadar, Dorina | van Boxtel, Martin P.J. | Verhey, Frans R.J. | Steptoe, Andrew | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Differences in dementia risk across the gradient of socioeconomic status (SES) exist, but their determinants are not well understood. Objective: This study investigates whether health conditions and lifestyle-related risk factors explain the SES inequalities in dementia risk. Methods: 6,346 participants from the English Longitudinal Study of Ageing were followed up from 2008/2009 until 2014/2015. We used Cox regression adjusted for age, gender, wealth/education, and clustering at the household level to examine the association between SES markers (wealth, education) and time to dementia in a structural equation model including potential mediation or effect modification by a …weighted compound score of twelve modifiable risk and protective factors for dementia (‘LIfestyle for BRAin health’ (LIBRA) score). Results: During a median follow-up of 6 years, 192 individuals (3.0%) developed dementia. LIBRA scores decreased with increasing wealth and higher educational level. A one-point increase in the LIBRA score was associated with a 13% increase in dementia risk (hazard ratio (HR) = 1.13, 95% confidence interval 1.07–1.19). Higher wealth was associated with a decreased dementia risk (HR = 0.58, 0.39–0.85). Mediation analysis showed that 52% of the risk difference between the highest and lowest wealth tertile was mediated by differences in LIBRA (indirect effect: HR = 0.75, 0.66–0.85). Education was not directly associated with dementia (HR = 1.05, 0.69–1.59), but was a distal risk factor for dementia by explaining differences in wealth and LIBRA scores (indirect effect high education: HR = 0.92, 0.88–0.95). Conclusion: Socioeconomic differences in dementia risk can be partly explained by differences in modifiable health conditions and lifestyle factors. Show more

Keywords: Aging, cohort study, dementia, epidemiology, health inequalities, lifestyle, mediation, prevention, public health, risk factors, socioeconomic status

DOI: 10.3233/JAD-190541

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Supasitthumrong, Thitiporn | Tunvirachaisakul, Chavit | Aniwattanapong, Daruj | Tangwongchai, Sookjaroen | Chuchuen, Phenphichcha | Tawankanjanachot, Itthipol | Snabboon, Thiti | Hemrungrojn, Solaphat | Carvalho, Andre F. | Maes, Michael

Article Type: Research Article

Abstract: Background: The Apolipoprotein E4 (ApoE4) genotype is strongly associated with Alzheimer’s disease (AD), although the presence of the ApoE4 allele alone is not sufficient to explain AD. The pathophysiology of amnestic mild cognitive impairment (aMCI) remains unclear. Objective: This study aims to examine associations between peripheral blood biomarkers coupled with ApoE4 and episodic and semantic memory. Methods: The CERAD battery was completed and various biomarkers were assayed in 60 subjects with aMCI, 60 with AD, and 62 healthy controls. Results: Deficits in semantic and episodic memory were significantly predicted by anion gap and bicarbonate, …albumin, and glucose coupled with ApoE4. Furthermore, these peripheral biomarkers interacted with ApoE to predict greater memory impairments. Conclusions: Peripheral blood biomarkers may interact with pathways related to ApoE4 to predict greater semantic and episodic memory impairments, thus contributing to the pathophysiology of aMCI and AD. Our data suggest that the transition from aMCI to AD could at least in some cases be associated with significant interactions between ApoE4 and those peripheral blood biomarkers. Show more

Keywords: Anion gap, apolipoprotein, biomarkers, dementia, episodic memory, inflammation

DOI: 10.3233/JAD-190114

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Hobel, Zachary | Isenberg, A. Lisette | Raghupathy, Dhvani | Mack, Wendy | Pa, Judy | for the Alzheimer’s Disease Neuroimaging Initiative | the Australian Imaging Biomarkers and Lifestyle flagship study of ageing

Article Type: Research Article

Abstract: Background: APOE ɛ 4 and sex have been linked to increased risk for conversion to Alzheimer’s disease (AD). However, the relationship between APOE ɛ 4 gene dose, sex, and AD biomarkers remains understudied. Objective: To investigate the effect of APOE ɛ 4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOE ɛ 4 dose modifies AD risk differently in MCI women and men. Methods: We examined cross-sectional AD biomarkers for participants with MCI (n  = 930, 55–96 years old) from three large …aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOE ɛ 4 alleles and stratified by sex. Results: Across all participants, number of APOE ɛ 4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOE ɛ 4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOE ɛ 4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOE ɛ 4 alleles. Women with 2 APOE ɛ 4 alleles had poorer memory between 65–69 and poorer global cognition between 70–74 compared to men with 2 APOE ɛ 4 alleles. Conclusion: APOE ɛ 4 confers a dose effect on AD biomarkers in patients with MCI, and the number of APOE ɛ 4 alleles has a greater detrimental impact in women than men, which may be specific to a critical time window. Show more

Keywords: Alzheimer’s disease, APOE, genetics, hippocampus, memory, mild cognitive impairment, MRI, sex effects

DOI: 10.3233/JAD-180859

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Showraki, Alireza | Murari, Geetanjali | Ismail, Zahinoor | Barfett, Joseph J. | Fornazzari, Luis | Munoz, David G. | Schweizer, Tom A. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are common, accelerate the conversion to dementia, and are associated with increased caregiver burden in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objective: The aim of this study is to identify potential associations between the core cerebrospinal fluid (CSF) biomarkers (amyloid/tau) and NPS in AD/MCI. Methods: For this systematic review, four databases, PubMed (1946–2018), Cochrane (2005–2018), EMBASE (1947–2018), and PsycINFO (1806–2018) were searched for relevant observational studies using an extensive list of keywords. English studies were selected for critical appraisal based on our inclusion/exclusion criteria. Inclusion criteria …were defined as 1) at least one AD CSF biomarker has been measured; 2) at least one NPS has been assessed; and 3) analysis has been done to examine the association between core AD CSF biomarker and NPS (main outcome). Animal, postmortem, and review studies were excluded. Results: In total, 21 studies qualified for the systematic review. The overall picture regarding the association between NPS and AD CSF biomarkers is conflicting. However, agitation/aggression was significantly and consistently related to core AD CSF biomarkers. Moreover, depression was the only NPS to occasionally be associated with lower core AD CSF pathology. Conclusion: Our study has revealed agitation/aggression as the most consistent NPS related to core AD CSF biomarkers. Future studies are required to focus on other neglected NPS domains such as disinhibition. Moreover, why depression was the only NPS inversely associated with core AD CSF pathology remains to be elucidated. Our study also revealed a great degree of heterogeneity, hence calling for a more standardized “objective” approach for the evaluation of NPS. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, biomarkers, cerebrospinal fluid, neuropsychiatry, systematic review

DOI: 10.3233/JAD-190365

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2019

Authors: Vaskivuo, Laura | Hokkanen, Laura | Hänninen, Tuomo | Antikainen, Riitta | Bäckman, Lars | Laatikainen, Tiina | Paajanen, Teemu | Stigsdotter-Neely, Anna | Strandberg, Timo | Tuomilehto, Jaakko | Soininen, Hilkka | Kivipelto, Miia | Ngandu, Tiia

Article Type: Research Article

Abstract: Background: Subjective memory complaints (SMCs) may be the first sign of cognitive decline in aging. Objective: To examine whether SMCs reported by oneself and informant predict cognitive change over 2 years among at-risk elderly people, and to determine the relationship of different types of SMCs (prospective and retrospective memory complaints) and change in cognitive function. Methods: This investigation is part of the FINGER project, which is a multicenter randomized controlled trial aiming at preventing cognitive decline in cognitively healthy older adults with increased risk of dementia. A subsample of 303 control-group participants (aged 60–80 years) and …their informants (n  = 261) rated the frequency of SMCs, using the Prospective and Retrospective Memory Questionnaire (PRMQ). Cognitive performance was measured at baseline and at 1- and 2-year follow-up visits using a neuropsychological test battery. Results: Participants who reported more SMCs improved less in global cognition, executive function, and memory during the subsequent 2 years in the fully-adjusted analyses. Self-reported retrospective memory problems predicted less improvement in all cognitive domains, whereas prospective memory problems did not. Informant-reported memory problems were not linked to subsequent change in cognition. Conclusion: Our results indicate that self-reported SMCs, measured with PRMQ, predict future cognitive change in several cognitive domains. By contrast, reports by informants were not linked to changes in cognition. Among cognitively healthy at-risk elderly individuals, the persons themselves observe more easily problems relevant for their future cognitive trajectories than their informants. Show more

Keywords: Aging, cognition, dementia, memory

DOI: 10.3233/JAD-190133

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Pavlik, Valory N. | Chan, Wenyaw | Darby, Eveleen

Article Type: Research Article

Abstract: Background: Accurate prediction of Alzheimer’s disease (AD) cognitive and functional outcomes in clinical research requires consistent underlying rates of change over time. Objective: To examine cohort effects in AD progression rate over five years of follow-up using a clinical database of probable AD patients. Methods: Baseline characteristics of three cohorts enrolled from 1995–1999, 2000–2004, and 2005–2009 were compared using ANOVA and chi-square tests. Differences in 5-year decline on the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Lawton and Brody Physical Self-maintenance Scale (PSMS), …and Activities of Daily Living Scale (ADL) were assessed using longitudinal mixed effects regression, adjusting for age, sex, education, and other relevant clinical characteristics. Results: Cohorts 1 (n  = 287), 2 (n  = 257), and 3 (n  = 374) did not differ on age, race, APOE genotype, or cognitive and functional measures. Educational attainment increased over time (13.4, 14.1, and 14.5 years, respectively, p  <  0.001). Anti-dementia drug use at baseline was less common in Cohort 1 (32.2% versus 65.0%, and 66.8%, p  <  0.001). The rate of decline in MMSE and CDR-SB did not differ across cohorts. ADAS-Cog scores for Cohort 2 declined more slowly than Cohort 3 (Btime ×cohort2  = -0.91 ± 0.35, p  = 0.009), whereas Cohort 1 did not differ from cohort 3 (reference). Cohorts 1 and 2 differed from Cohort 3 in progression rate on the PSMS, but not the IADL. Conclusions: There were no consistent temporal trends in progression rates over time. Longitudinal data over 15–20 years may be confidently pooled for outcomes analysis, but unexplained variability in rate of decline on some measures may occur. Show more

Keywords: Alzheimer’s disease, cognitive decline, cohort effects, disease progression

DOI: 10.3233/JAD-190661

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Ruano, Luis | Severo, Milton | Sousa, Andreia | Ruano, Catarina | Branco, Mariana | Barreto, Rui | Moreira, Sandra | Araújo, Natália | Pinto, Paula | Pais, Joana | Lunet, Nuno | Cruz, Vítor Tedim

Article Type: Research Article

Abstract: Repeated measurements could be helpful to identify patients with early cognitive decline. We compare the variation of cognitive performance over one year in patients with mild cognitive impairment (MCI) and healthy individuals using the Brain on Track self-applied computerized test (BoT). The study was initiated 30 patients with probable MCI and 377 controls from a population-based cohort, who performed the BoT test from home every three months for one year. The scores were compared using a linear mixed-effects model. All participants increased their scores in the first tests, after 120 days MCI patients started to decline, with a statistically significant …higher rate. The area under the curve to detect MCI was 0.94. We identified a significant decline in cognitive performance over one year in patients with MCI using BoT and the test presented a high discriminative ability. Show more

Keywords: Cognition disorders, cognitive screening, computer-assisted decision making, dementia, mild cognitive impairment

DOI: 10.3233/JAD-190631

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Liang, Tao | Xue, Feixiao | Hang, Weijian | Wen, Bin | Zhang, Qianying | Chen, Jiehui | Liu, Xiaofeng | Chen, Juan

Article Type: Research Article

Abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD). It is shown that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated apoE4 fragment. Endoplasmic reticulum (ER) stress has also been known to be involved in the pathogenesis of AD. However, little is known about the contribution of ER stress to the neurotoxicity of apoE4 fragment. In the present study, we established the neuron-specific expression human C-terminal-truncated apoE4(1–272) fragment transgenic mice and also transfected apoE4(1–272) fragment in neuroblastoma N2a cells. We found that human apoE4(1–272) fragment could trigger ER stress as evidenced by increasing the …expression of ER stress markers both in vivo and in vitro . Meanwhile, the apoE4(1–272) transgenic mice presented obviously AD-like neuropathological changes, including the impairment of spatial learning and memory, prominent axonal morphological changes, and hyperphosphorylation of tau. At the same time, we also found that glycogen synthase kinase-3 activities were significantly increased. Furthermore, these neuropathological changes, especially tau hyperphosphorylation and axonal transport impairment, were significantly rescued by the ER stress protector 4-phenylbutyric acid (4-PBA) in apoE4(1–272)-transfected N2a cells. Pretreatment with 4-PBA not only decreased the protein expression of immunoglobulin binding protein (BiP) and C/EBP-homologous protein (CHOP), but also significantly reversed these defects in axonal transport. These results suggested that the neurotoxic effects of apoE4(1–272) fragment found in AD subjects, at least in part, through triggering ER stress and inducing tau hyperphosphorylation, led to the enduring impairment of axonal transport. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4 (1–272), axonopathy, endoplasmic reticulum stress, tau phosphorylation

DOI: 10.3233/JAD-190419

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Pirker-Kees, Agnes | Dal-Bianco, Peter | Schmidt, Reinhold

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia are common in Alzheimer’s disease (AD) and associated with a more rapid decline in cognitive function. Psychotropic substances are frequently used in AD, but we lack conclusive evidence of their efficacy in this setting. SSRI and trazodone were reported to have positive effects on cognition. Based on the prospective registry of dementia in Austria (PRODEM), we investigated the effects of psychotropic substances on cognition, behavioral symptoms, and caregiver burden (CB) in patients with AD, followed up prospectively over a 12-month period. We used the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the …Zarit caregiver burden interview. The study cohort consisted of 309 patients. Patients taking no psychotropic drugs (NO) or those undergoing consistent monotherapy with a psychotropic drug for 12 months were analyzed further (NO 101 patients, SSRI 22, trazodone 8, atypical neuroleptics or benzodiazepines (ANL/BZD) 18). Additionally, the subgroup of patients who started taking any of the substances during the study period were analyzed further to determine the effects before versus six months after the start of medication. MMSE, NPI, and CB at baseline and during follow-up did not differ between the groups. MMSE and CB declined over 12 months in the overall group (MMSE: 21.2±4 versus 19.7±5, p  = 0.001 and CB 20.3±12 versus 24.7±14.2, p  = 0.007), but no statistically significant changes were registered within groups over 12 months. When trazodone was started, only NPI improved significantly after 6 months (33.4±18 versus 18.9±22.7, p  <  0.01). ANL/BZD or SSRI, when started, did not alter MMSE, NPI, or CB. SSRI had no beneficial effect on cognition. We conclude that trazodone might be helpful in the treatment of behavioral symptoms. Show more

Keywords: Alzheimer’s disease, behavioral, caregiver, psychotropic drugs

DOI: 10.3233/JAD-181102

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Su, Ning | Liang, Xinyu | Yao, Ming | Zhou, Li-Xin | Wang, Quan | Jin, Zheng-Yu | Zhang, Shu-Yang | Cui, Li-Ying | Gong, Gaolang | Zhu, Yi-Cheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Few studies have investigated the correlation between cerebral microbleeds (CMBs), a hemorrhagic imaging marker of cerebral small vessel disease (CSVD), and brain volume. Objective: We investigated the association between the burden and locations of CMBs and brain volume in community-dwelling populations. Methods: Data were obtained from 1,029 participants who underwent brain magnetic resonance imaging (MRI) and APOE genotyping. Volumes of the whole brain, subcortical white matter (WM), cortical gray matter (GM), and hippocampus were extracted. Linear regression models were used to investigate the relationship between the CMB burden and their location with structural changes. …Results: Regarding burden, participants with≥3 CMBs had significantly lower whole brain (β = –1.124, p  = 0.0133), subcortical WM (β = –1.020, p  = 0.0043), and hippocampus (β = –0.015, p  = 0.0088) volumes than those without CMBs. Regarding location and burden, the presence of≥3 strictly lobar CMBs was negatively associated with whole brain volume (β = –2.838, p  = 0.0088). Additionally, higher CMB burdens in strictly lobar locations or deep/mixed locations were associated with lower subcortical WM volume (β = –1.689, p  = 0.0482; β = –0.872, p  = 0.0464, respectively). Finally, the presence of≥3 deep/mixed CMBs was associated with lower hippocampus volume (β = –0.018, p  = 0.0088), and these associations were independent of other ischemic markers of CSVD. However, the CMB burden and distributional pattern did not correlate with cortical GM volumes. Conclusion: A higher CMB burden, in specific locations, is associated with decreased brain volumes in community-dwelling populations. Show more

Keywords: brain volumes, cerebral microbleeds, cerebral small vessel disease, hippocampus, white matter

DOI: 10.3233/JAD-190454

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Martin, Donel M. | Mohan, Adith | Alonzo, Angelo | Gates, Nicola | Gbadeyan, Oyetunde | Meinzer, Marcus | Sachdev, Perminder | Brodaty, Henry | Loo, Colleen

Article Type: Research Article

Abstract: Background: There is currently no effective intervention for improving memory in people at increased risk for dementia. Cognitive training (CT) has been promising, though effects are modest, particularly at follow-up. Objective: To investigate whether adjunctive non-invasive brain stimulation (transcranial direct current stimulation, tDCS) could enhance the memory benefits of CT in amnestic mild cognitive impairment (aMCI). Methods: Participants with aMCI were randomized to receive CT with either Active tDCS (2 mA for 30 min and 0.016 mA for 30 min) or Sham tDCS (0.016 mA for 60 min) for 15 sessions over a period of 5 weeks in a double-blind, sham-controlled, parallel …group clinical trial. The primary outcome measure was the California Verbal Learning Task 2nd Edition. Results: 68 participants commenced the intervention. Intention-to-treat (ITT) analysis showed that the CT+Active tDCS group significantly improved at post treatment (p  = 0.033), and the CT+Sham tDCS group did not (p  = 0.050), but there was no difference between groups. At the 3-month follow-up, both groups showed large-sized memory improvements compared to pre-treatment (CT+Active tDCS: p  < 0.01, d  = 0.99; CT+Sham tDCS: p  < 0.01, d  = 0.74), although there was no significant difference between groups. Conclusion: This study found that CT+Active tDCS did not produce greater memory improvement compared to CT+Sham tDCS. Large-sized memory improvements occurred in both conditions at follow-up. One possible interpretation, based on recent novel findings, is that low intensity tDCS (used as ‘sham’) may have contributed biological effects. Further work should use a completely inert tDCS sham condition. Show more

Keywords: cognitive training, memory, mild cognitive impairment, randomized controlled trial, transcranial direct current stimulation, treatment

DOI: 10.3233/JAD-190306

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Qiu, Ruolun | Ahn, Jae Eun | Alexander, Robert | Brodney, Michael A. | He, Ping | Leurent, Claire | Mancuso, Jessica | Margolin, Richard A. | Tankisheva, Ekaterina | Chen, Danny

Article Type: Research Article

Abstract: PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-β (Aβ ) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer’s disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events …(AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aβ peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aβ 1–40 and Aβ 1–42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, BACE1 protein-human, pharmacodynamics, pharmacokinetics, Phase I, safety, tolerability

DOI: 10.3233/JAD-190228

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Tarumi, Takashi | Rossetti, Heidi | Thomas, Binu P. | Harris, Thomas | Tseng, Benjamin Y. | Turner, Marcel | Wang, Ciwen | German, Zohre | Martin-Cook, Kristin | Stowe, Ann M. | Womack, Kyle B. | Mathews, Dana | Kerwin, Diana R. | Hynan, Linda | Diaz-Arrastia, Ramon | Lu, Hanzhang | Munro Cullum, C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). Objective: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-β (Aβ ) plaque deposition in aMCI patients. Methods: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and …the Delis–Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aβ deposition. Results: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aβ plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. Conclusion: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aβ deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group. Show more

Keywords: Aerobic exercise, amyloid deposition, brain volume, cardiovascular fitness, mild cognitive impairment

DOI: 10.3233/JAD-181175

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Quan, Qiankun | Qian, Yihua | Li, Xi | Li, Ming

Article Type: Research Article

Abstract: Cyclin-dependent kinase 5 (CDK5) in adipose tissue mediates peroxisome proliferator-activated receptor γ (PPARγ ) phosphorylation at Ser273 to inhibit its activity, causing PPARγ target gene expression changes. Among these, insulin-degrading enzyme (IDE) degrades amyloid-β peptide (Aβ), the core pathological product of Alzheimer’s disease (AD), whereas β-amyloid cleavage enzyme 1 (BACE1) hydrolyzes amyloid-β protein precursor (AβPP). Therefore, we speculated that CDK5 activity in the brain might participate in Aβ production, thereby functioning as a key molecule in AD pathogenesis. To confirm this hypothesis, we transduced primary rat hippocampal neurons using CDK5-expressing lentiviral vectors. CDK5 overexpression increased PPARγ Ser273 …phosphorylation, decreased IDE expression, increased BACE1 and AβPP expression, increased Aβ levels, and induced neuronal apoptosis. The CDK5 inhibitor roscovitine effectively reversed these CDK5 overexpression-mediated effects. Moreover, silencing of the Cdk5 gene via CDK5 shRNA-expressing lentiviral vectors in primary hippocampal neurons did not exert any protective effect against normal neuronal apoptosis, nor were significant effects observed on Aβ levels, PPARγ phosphorylation, or PPARγ target gene expression in the cells. However, Cdk5 gene silencing exhibited a neuroprotective effect in the Aβ-induced AD neuron model by effectively inhibiting the Aβ-induced neuronal apoptosis, PPARγ phosphorylation, PPARγ expression downregulation, and PPARγ target gene expression changes, and reducing Aβ levels. In conclusion, this study demonstrated that CDK5 played an important role in the pathogenesis of AD. Specifically, CDK5 participated in Aβ production by regulating PPARγ phosphorylation. Targeted therapy against CDK5 could effectively reduce and reverse the neurotoxic effects of Aβ and may represent a novel approach for AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid, cyclin-dependent kinase 5, peroxisome proliferator-activated receptors, phosphorylation

DOI: 10.3233/JAD-190026

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Xiong, Li | Charidimou, Andreas | Pasi, Marco | Boulouis, Gregoire | Pongpitakmetha, Thanakit | Schirmer, Markus D. | Singh, Sanjula | Benson, Emily | Gurol, Edip M. | Rosand, Jonathan | Greenberg, Steven M. | Biffi, Alessandro | Viswanathan, Anand

Article Type: Research Article

Abstract: Background and Objective: Cerebral amyloid angiopathy (CAA) accounts for the majority of lobar intracerebral hemorrhage (ICH); however, the risk factors for dementia conversion after ICH occurrence in CAA patients is unknown, especially in the long-term period after ICH. Therefore, we aimed to unravel the predictors for late post-ICH dementia (6 months after ICH event) in probable CAA patients. Methods: From a large consecutive MRI prospective cohort of spontaneous ICH (2006–2017), we identified probable CAA patients (modified Boston criteria) without dementia 6 months post-ICH. Cognitive outcome during follow-up was determined based on the information from standardized clinical visit notes. …We used Cox regression analysis to investigate the association between baseline demographic characteristics, past medical history, MRI biomarkers, and late post-ICH dementia conversion (dementia occurred after 6 months). Results: Among 97 non-demented lobar ICH patients with probable CAA, 25 patients (25.8%) developed dementia during a median follow-up time of 2.5 years (IQR 1.5–3.8 years). Pre-existing mild cognitive impairment, increased white matter hyperintensities (WMH) burden, the presence of disseminated cortical superficial siderosis (cSS), and higher total small vessel disease score for CAA were all independent predictors for late dementia conversion. Conclusion: In probable CAA patients presenting with lobar ICH, high WMH burden and presence of disseminated cSS are useful neuroimaging biomarkers for dementia risk stratification. These findings have implications for clinical practice and future trial design. Show more

Keywords: Cerebral amyloid angiopathy, cerebral hemorrhage, cerebral small vessel disease, dementia

DOI: 10.3233/JAD-190346

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Zhu, Wenhao | Huang, Hao | Yang, Shiqi | Luo, Xiang | Zhu, Wenzhen | Xu, Shabei | Meng, Qi | Zuo, Chengchao | Zhao, Kun | Liu, Hesheng | Liu, Yong | Wang, Wei

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) are common in older adults and are associated with cognitive decline. However, little is known about the functional changes underlying cognitive decline in WMH subjects. Objectives: To investigate whole-brain functional connectivity (FC) underpinnings of cognitive decline in WMH subjects using univariate and multivariate analyses. Methods: Twenty-three WMH subjects with mild cognitive impairment (WMH-MCI), 43 WMH subjects with no cognitive impairment (WMH-nCI), and 55 healthy controls underwent resting-state functional MRI scans. Whole-brain FC was calculated using the fine-grained human Brainnetome Atlas, followed by performance of between-group comparisons and FC-cognition correlation analysis. A …multivariate analysis using support vector machine (SVM) was performed to classify WMH-MCI and WMH-nCI subjects based on FC. Results: Both the WMH-MCI and WMH-nCI subjects exhibited characteristic impaired FC patterns. Markedly reduced FC involving subcortical nuclei and cortical hub regions of cognitive networks, especially the cingulate cortex, was identified in the WMH-MCI patients. In the WMH-MCI group, several connections involving the cingulate cortex were associated with cognitive decline. The exploratory mediation analyses indicated that FC alterations could partially explain the association between WMH and cognition. Furthermore, an SVM classifier based on FC distinguished WMH-MCI and WMH-nCI subjects with 78.8% accuracy. Connections that contributed most to the classification showed a similar distribution as the connections identified in the univariate analysis. Conclusions: This study provides a new window into the pathophysiology of cognitive impairment in WMH subjects and offer a novel and potential approach for early detection of the cognitive impairment in WMH subjects at the individual level. Show more

Keywords: Functional connectivity, mild cognitive impairment, resting-state functional MRI, support vector machine, white matter hyperintensities

DOI: 10.3233/JAD-190174

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Attier-Zmudka, Jadwiga | Sérot, Jean-Marie

Article Type: Editorial

Abstract: After World War I and more particularly in June 1940, the prestige of French Marshal Philippe Pétain, considered as the winning general the battle of Verdun, was very high. He became President of Council while the French army was unable to stop the German offensives. But five years later he was sentenced to death for high treason. By rereading his bibliography from a medical perspective, it is possible to find multiple suggestive events and to affirm a posteriori Pétain suffered from a neurodegenerative disorder, whose first signs appeared in the 1930s, suggestive of Alzheimer’s disease, which had an impact …on French politics. The modern medical knowledge of this disease casts a new light on the behavior of Petain during the last war. Show more

Keywords: Alzheimer’s disease, dementia, neurocognitive syndrome, pétain

DOI: 10.3233/JAD-190225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Abbate, Carlo | Trimarchi, Pietro D. | Inglese, Silvia | Damanti, Sarah | Dolci, Giulia A.M. | Ciccone, Simona | Rossi, Paolo D. | Mari, Daniela | Arosio, Beatrice | Bagarolo, Renzo | Giunco, Fabrizio | Cesari, Matteo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated. Objective: To explore the existence of focal RAD on the basis of existing literature. Methods: We performed a literature search …for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD. Results: Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome. Conclusion: Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition. Show more

Keywords: Alzheimer’s disease, cognitive manifestations, left right asymmetry, right Alzheimer’s disease, right hemisphere, syndromic diversity, variant of Alzheimer’s disease, visuospatial ORCID: 0000-0002-0368-3834

DOI: 10.3233/JAD-190338

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Maher, Barbara A.

Article Type: Review Article

Abstract: Fewer than 5% of Alzheimer’s disease (AD) cases are demonstrably directly inherited, indicating that environmental factors may be important in initiating and/or promoting the disease. Excess iron is toxic to cells; iron overload in the AD brain may aggressively accelerate AD. Magnetite nanoparticles, capable of catalyzing formation of reactive oxygen species, occur in AD plaques and tangles; they are thought to form in situ, from pathological iron dysfunction. A recent study has identified in frontal cortex samples the abundant presence of magnetite nanoparticles consistent with high-temperature formation; identifying therefore their external, not internal source. These magnetite particles range from ∼10 …to 150 nm in size, and are often associated with other, non-endogenous metals (including platinum, cadmium, cerium). Some display rounded crystal morphologies and fused surface textures, reflecting cooling and crystallization from an initially heated, iron-bearing source material. Precisely-matching magnetite ‘nanospheres’ occur abundantly in roadside air pollution, arising from vehicle combustion and, especially, frictional brake-wear. Airborne magnetite pollution particles < ∼200 nm in size can access the brain directly via the olfactory and/or trigeminal nerves, bypassing the blood-brain barrier. Given their toxicity, abundance in roadside air, and nanoscale dimensions, traffic-derived magnetite pollution nanoparticles may constitute a chronic and pernicious neurotoxicant, and hence an environmental risk factor for AD, for large population numbers globally. Olfactory nerve damage displays strong association with AD development. Reported links between AD and occupational magnetic fields (e.g., affecting welders, machinists) may instead reflect inhalation exposure to airborne magnetic nanoparticles. Show more

Keywords: Air pollution, alzheimer’s disease, inhalation exposure, iron overload, magnetite nanoparticles, metal nanoparticles

DOI: 10.3233/JAD-190204

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Mendez, Mario F.

Article Type: Review Article

Abstract: Despite the large number of elderly bilinguals at risk for Alzheimer’s disease (AD) and dementia worldwide, significant questions remain about the relationship between speaking more than one language and later cognitive decline. Bilingualism may impact on cognitive and neural reserve, time of onset of dementia symptoms and neuropathology, and linguistic competency in dementia. This review indicates increased cognitive reserve from executive (monitoring, selecting, inhibiting) control of two languages and increased neural reserve involving left frontal and related areas for language control. Many, but not all, studies indicate a delay in dementia symptom onset but worse hippocampal and mesiotemporal atrophy among …bilinguals versus monolinguals with AD. In contrast, bilinguals do worse on language measures, and bilinguals with AD or dementia have difficulty maintaining and monitoring their second language. Together, these studies suggest that early-acquired and proficient bilingualism increases reserve through frontal-predominant executive control, and these executive abilities compensate for early dementia symptoms, delaying their onset but not the neuropathology of their disease. Finally, as executive control decreases further with advancing dementia, there is increasing difficulty inhibiting the dominant first language and staying in the second language. These conclusions must be interpreted with caution, given the problems inherent in this type of research; however, they do recommend more work on the pre-dementia neuroprotective effects and the dementia-related language impairments of bilingualism. Show more

Keywords: Alzheimer’s disease, bilingualism, dementia, language

DOI: 10.3233/JAD-190397

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Cullen, Stephanie | Borrie, Michael | Carroll, Susan | Sarquis-Adamson, Yanina | Pieruccini-Faria, Frederico | McKay, Scott | Montero-Odasso, Manuel

Article Type: Research Article

Abstract: Background: Poor dual-task gait (walking while performing a cognitively demanding task) has been linked to progression to dementia in older adults with mild cognitive impairment (MCI). However, many of these findings come from research environments; gait performance across the cognitive spectrum has not previously been studied in a clinical setting. Objective: To examine whether patients from a memory clinic show differences in usual and dual-task gait speed and dual-task cost (DTC) based on cognitive diagnosis. Methods: Patients in the Aging Brain Memory clinic (London, ON) performed a usual gait walk and three dual-task gait walks: counting …backwards by ones, naming animals, and counting backwards by seven (serial sevens) out loud. Patients were timed with a stopwatch over a six-meter path marked on the floor. One-way ANOVA was performed to evaluate associations between gait speed and DTC (% ) across groups. Results: One hundred ninety-four patients with subjective cognitive impairment (SCI; n  = 46), MCI (n  = 77), or dementia (n  = 71) were assessed. Performance in usual (p  <  0.001) and dual-task gait speed (counting gait p  <  0.001; naming animals p  <  0.001; serial sevens p  = 0.004) decreased across the spectrum of cognitive impairment. Patients with dementia had significantly higher DTC in both counting gait (p  = 0.02) and naming animals (p  = 0.04) conditions compared with patients with SCI and MCI, who had statistically similar DTC in all conditions. Conclusion: Dual-task gait performance significantly declines across the cognitive spectrum in a clinical setting. Dual-task gait testing may be used in conjunction with traditional assessments for diagnosing cognitive impairments. Show more

Keywords: Aging, cognition, dual-task gait, gait

DOI: 10.3233/JAD-181196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Nocera, Joe R. | Arsik, Idil | Keskinocak, Pinar | Lepley-Flood, Amy | Lah, James J. | Levey, Allan I. | Esper, Greg J.

Article Type: Short Communication

Abstract: There is increasing interest in gait evaluations in clinical settings given the associations between gait and health outcomes. However, efforts examining implementation of gait evaluation in neurological clinics are lacking. Herein, gait implementation within a cognitive neurology clinic is presented. Over a 21-month period, a gait evaluation was collected on 81% of eligible patients (n  = 2,622; mean age 73.2±9.5; age range 49–94 years; 47% female). Patients and staff reported being satisfied with the gait assessment. These finding have implications for gait evaluations in clinical settings and for clinical research aimed at understanding the impact of cognitive symptomatology on gait.

Keywords: Cognition, dementia, gait, implementation

DOI: 10.3233/JAD-190106

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Mattos, Meghan K. | Sereika, Susan M. | Beach, Scott R. | Kim, Hyejin | Klunk, William E. | Knox, Melissa | Nadkarni, Neelesh K. | Parker, Lisa S. | Roberts, J. Scott | Schulz, Richard | Tamres, Lisa | Lingler, Jennifer H.

Article Type: Review Article

Abstract: As calls for transparency in human subjects research grow, investigators conducting Alzheimer’s disease (AD) biomarker research are increasingly required to consider their ethical obligations regarding the return of AD biomarker test results to research participants. When disclosing these test results to potentially vulnerable participants, investigators may face unique challenges to identify adverse events, particularly psychological events. The purpose of this paper is to describe our research team’s experience with developing and implementing a process for enhanced adverse event monitoring following the return of amyloid-β (Aβ) imaging results to research participants with mild cognitive impairment (MCI). Ethical and logistical considerations are …presented along with preliminary findings from an ongoing randomized controlled trial of Aβ imaging results disclosure in MCI. Following receipt of amyloid imaging results, participants underwent 14 days of adverse event monitoring using ecological momentary assessment (EMA), a strategy to capture health, behaviors, and mood as they occur in participants’ natural settings in real time. EMA telephone calls were placed at random during waking hours to screen for mood changes. Investigators were alerted for positive depression, anxiety, suicidal ideation screenings, or for two days of failed call attempts. Preliminary feasibility of twenty-four participants with MCI who participated in EMA mood assessments was successfully completed 83% (SD = 0.4) of the time over 14 days with no alerts for anxiety or depression screening items. EMA, when used with standard adverse event monitoring, is a promising and novel approach to maximize early detection of negative psychological reactions following AD biomarker results disclosed in research settings. Show more

Keywords: Amyloid, cognitive dysfunction, ecological momentary assessment, ethics, research subjects

DOI: 10.3233/JAD-190091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Parodi-Rullán, Rebecca | Sone, Je Yeong | Fossati, Silvia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and …brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure. Show more

Keywords: Alzheimer’s disease, amyloid, apoptosis, blood-brain barrier, cerebral amyloid angiopathy, endothelial cells, mitochondria, neurodegeneration, reactive nitrogen species, reactive oxygen species

DOI: 10.3233/JAD-190357

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2019

Authors: Toots, Annika T.M. | Taylor, Morag E. | Lord, Stephen R. | Close, Jacqueline C.T.

Article Type: Research Article

Abstract: Background: While gait has been linked with cognition, few studies have contrasted the strength of the relationships between gait speed and cognitive domains in people with cognitive impairment (CI). Objectives: Investigate the association between gait speed and global cognitive function and cognitive domains in older people with CI. Method: Three-hundred-and-nine community-dwelling people with CI (mean age 82 years, 47% female, and mean gait speed 0.62±0.23 m/s) were included using baseline data from the Intervention-Falls in Older Cognitively Impaired Study (iFOCIS). Usual gait speed (m/s) was measured over 2.4 m. Global cognitive function and individual cognitive domains (attention; …memory; verbal fluency; language; visuospatial ability) were assessed using the Addenbrooke’s Cognitive Examination-III (ACE-III). Additionally, executive function was assessed using the Frontal Assessment Battery (FAB). Results: Participants mean±standard deviation ACE-III and FAB scores were 62.8±19.3 and 11.4±4.6, respectively. In separate multiple linear regression analyses adjusting for confounders, global cognitive function, and each cognitive domain, was significantly associated with gait speed. Executive function demonstrated the strongest association (FAB: standardized β= 0.278, p  < 0.001, adjusted R2  = 0.431), and remained significantly associated with gait speed when adjusted for attention, memory, language, and visuospatial ability. Conclusion: In this large study of older people with CI, global cognition and each cognitive domain were associated with gait speed. Executive function had the strongest association, possibly reflecting the higher-level cognitive processes and complex motor task responses required for gait control. Future longitudinal studies are needed to explore the temporal relationships between declines in executive function and gait, and whether the facilitation of executive function lessens gait decline. Show more

Keywords: Aged, cognition, dementia, executive function, gait, walking speed

DOI: 10.3233/JAD-181173

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Taylor, Morag E. | Brodie, Matthew A. | van Schooten, Kimberley S. | Delbaere, Kim | Close, Jacqueline C.T. | Payne, Narelle | Webster, Lyndell | Chow, Jessica | McInerney, Garth | Kurrle, Susan E. | Lord, Stephen R.

Article Type: Research Article

Abstract: Understanding the characteristics of physical activity and daily-life gait in older people with dementia may help identify those at risk of negative health outcomes and inform targeted interventions. Questionnaires are often used to assess physical activity but may be more affected by recall bias in people with dementia and provide little information about daily-life gait characteristics. The aim of the study was to assess differences in daily-life activity levels and gait characteristics between community-dwelling older people with mild to moderate dementia (n  = 45; mean age 81±6 years, 42% female) and age-sex matched (1:2) cognitively-healthy controls (n  = 90). Participants wore a …tri-axial accelerometer (DynaPort MoveMonitor, McRoberts) on their lower back for 7 days and were assessed on neuropsychological and physical performance. Compared to age-sex matched controls, participants with dementia demonstrated reduced daily-life activity (fewer steps per day, fewer and shorter walking bouts, and lower daily walk time) and walking intensity (reduced speed, stride length and cadence). Participants with dementia also had significantly increased within-walk variability (stride time) and less regular gait (higher sample entropy). Within the group of participants with dementia, higher daily-life activity levels were associated with greater self-reported physical activity and better executive function. Fallers (1+ falls past year) with dementia had significantly reduced daily-life activity and walking speed when compared to non-fallers with dementia. In conclusion, people with dementia are less active in daily-life and present with significant impairments across multiple gait domains when compared to age-sex matched controls. These findings highlight opportunities for targeted interventions and support further research to examine interventions aimed at addressing these deficits. Show more

Keywords: Accidental falls, daily-life gait, dementia, executive function, neurocognitive disorders, physical activity, walking speed

DOI: 10.3233/JAD-181174

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Lejri, Imane | Grimm, Amandine | Hallé, François | Abarghaz, Mustapha | Klein, Christian | Maitre, Michel | Schmitt, Martine | Bourguignon, Jean-Jacques | Mensah-Nyagan, Ayikoe Guy | Bihel, Frederic | Eckert, Anne

Article Type: Research Article

Abstract:  Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer’s disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro . In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects …of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease. Show more

Keywords: Alzheimer’s disease, bioenergetics phenotype, mitochondria, neuroprotection, oxidative stress, pregnenolone, TSPO ligands

DOI: 10.3233/JAD-190127

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: George, Elizabeth Kurudamannil | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of …total AD patients can be explained by genetic mutations in APP , PS1 , and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state. Show more

Keywords: Alzheimer’s disease, amyloid-beta, antioxidant enriched diet, healthcare cost, healthy diets, mitochondria, phosphorylated tau, reactive oxygen species, regular exercise

DOI: 10.3233/JAD-190232

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2019

Authors: Hunter, Susan W. | Divine, Alison | Omana, Humberto | Wittich, Walter | Hill, Keith D. | Johnson, Andrew M. | Holmes, Jeffrey D.

Article Type: Research Article

Abstract: Background: Cognitive deficits and gait problems are common and progressive in Alzheimer’s disease (AD). Prescription of a 4-wheeled walker is a common intervention to improve stability and independence, yet can be associated with an increased falls risk. Objectives: 1) To examine changes in spatial-temporal gait parameters while using a 4-wheeled walker under different walking conditions, and 2) to determine the cognitive and gait task costs of walking with the aid in adults with AD and healthy older adults. Methods: Twenty participants with AD (age 79.1±7.1 years) and 22 controls (age 68.5±10.7 years) walked using a 4-wheeled …walker in a straight (6 m) and Figure of 8 path under three task conditions: single-task (no aid), dual-task (walking with aid), and multi-task (walking with aid while counting backwards by ones). Results: Gait velocity was statistically slower in adults with AD than the controls across all conditions (all p values <0.025). Stride time variability was significantly different between groups for straight path single task (p  = 0.045), straight path multi-task (p  = 0.031), and Figure of 8 multi-task (0.036). Gait and cognitive task costs increased while multi-tasking, with performance decrement greater for people with AD. None of the people with AD self-prioritized gait over the cognitive task while walking in a straight path, yet 75% were able to shift prioritization to gait in the complex walking path. Conclusion: Learning to use a 4-wheeled walker is cognitively demanding and any additional tasks increases the demands, further adversely affecting gait. The increased cognitive demands result in a decrease in gait velocity that is greatest in adults with AD. Future research needs to investigate the effects of mobility aid training on gait performance. Show more

Keywords: Aged, gait, assistive devices, cane, dementia

DOI: 10.3233/JAD-181170

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Allali, Gilles | Montembeault, Maxime | Saj, Arnaud | Wong, Chek Hooi | Cooper-Brown, Liam Anders | Bherer, Louis | Beauchet, Olivier

Article Type: Research Article

Abstract: Background: Gait impairment is observed in early stages of dementia, such as mild cognitive impairment (MCI), and is associated with morphological brain volume changes like atrophy. Objective: This study aims to characterize the brain’s grey matter (GM) volume covariance associated with gait speed in patients with amnestic mild cognitive impairment (aMCI) and non-amnestic MCI (naMCI). Methods: Gait speed was measured in 170 patients with MCI (age 72.0±5.1; 36.8% female; 41 with aMCI and 130 naMCI) at normal and rapid gait speeds. Brain GM covariance networks were computed using voxel-based morphometry, using the main neural correlates of …gait speed in each group and for each walking condition as seed regions. Results: Normal gait speed correlated with GM volume in the left frontal cortex in patients with aMCI, and in bilateral caudate and left putamen in those with naMCI. Rapid gait speed correlated with GM volume in the bilateral caudate and right cerebellum in naMCI, but without any GM region in aMCI. For normal gait speed, the left caudate nucleus volume in naMCI covaried with subcortico-frontal regions, while the left frontal cortex covaried with cortical regions involving the frontal cortex in aMCI. For rapid gait speed, subcortico-frontal regions were similar as for normal speed in naMCI. Conclusion: Brain GM volume covariance associated with gait speed varies according to the type of MCI; it involved subcortico-frontal regions for patients with naMCI and the frontal cortex in those with aMCI. Show more

Keywords: Alzheimer’s disease, anatomical structural covariance, gait, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-190038

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Hunter, Susan W. | Divine, Alison | Omana, Humberto | Wittich, Walter | Hill, Keith D. | Johnson, Andrew M. | Holmes, Jeffrey D.

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (AD) exhibit balance and walking impairments that increase falls risk. Prescription of a mobility aid is done to improve stability, yet also requires increased cognitive resources. Single-point canes require unique motor sequencing for safe use. The effect of learning to use a single-point cane has not been evaluated in people with AD. Objectives: In people with AD and healthy adult controls: 1) examine changes in gait while using a cane under various walking conditions; and 2) determine the cognitive and gait costs associated with concurrent cane walking while multi-tasking. Methods: Seventeen …participants with AD (age 82.1±5.6 years) and 25 healthy controls (age 70.8±14.1 years) walked using a single-point cane in a straight (6 meter) and a complex (Figure of 8) path under three conditions: single-task (no aid), dual-task (walking with aid), and multi-task (walking with aid while counting backwards by ones). Velocity and stride time variability were recorded with accelerometers. Results: Gait velocity significantly slowed for both groups in all conditions and stride time variability was greater in the AD group. Overall, multi-tasking produced a decrease in gait and cognitive demands for both groups, with more people with AD self-prioritizing the cognitive task over the gait task. Conclusion: Learning to use a cane demands cognitive resources that lead to detrimental changes in velocity and stride time variability. This was most pronounced in people with mild to moderate AD. Future research needs to investigate the effects of mobility aid training on gait performance. Show more

Keywords: Aged, assistive devices, cane, dementia, gait

DOI: 10.3233/JAD-181169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Reddy, P. Hemachandra | Swerdlow, Russell H. | Culberson, John | Kang, David | Mitchell, Tedd L. | Smith, Quentin | Suneja, Sanoj | Ory, Marcia G. | Kumar, Subodh | Vijayan, Murali | Morsy, Ahmed | Arandia, Gabriela | Lawrence, J. Josh | George, Elizabeth | Oliver, Darryll | Pradeepkiran, Jangampalli Adi | Yin, Xiangling | Reddy, Arubala P. | Manczak, Maria | Cengiz, Pelin | Karamyan, Vardan T. | Kandimalla, Ramesh | Kuruva, Chandra Sekhar | Willms, Joshua | Ramasubramanian, Bhagavathi | Sawant, Neha | Burugu, Divya | Boles, Annette N. | Lopez, Veronica | Carrasco, Rocio | Aguirre, Cordelia | Thompson, Susan | Blackmon, Joan | Ament, Clay | Wang, Rui | Stephens, Emily R. | Hoang, Brittney | Bass, Kevin | Trippier, Paul C. | Hornback, Christopher | Kottapalli, Pratibha | Kottapalli, Kameswara Rao | Center Biotechnology and Genetics Core Facility | Oddo, Salvatore

Article Type: Abstract

Abstract: The purpose of the ‘First Regional Healthy Aging and Dementia Research Symposium’ was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24–25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members …involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion. Show more

DOI: 10.3233/JAD-190252

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2019

Authors: Åhman, Hanna Bozkurt | Giedraitis, Vilmantas | Cedervall, Ylva | Lennhed, Björn | Berglund, Lars | McKee, Kevin | Kilander, Lena | Rosendahl, Erik | Ingelsson, Martin | Åberg, Anna Cristina

Article Type: Research Article

Abstract: Background: Tools to identify individuals at preclinical stages of dementia disorders are needed to enable early interventions. Alterations in dual-task performance have been detected early in progressive neurodegenerative disorders. Hence, dual-task testing may have the potential to screen for cognitive impairment caused by neurodegeneration. Exploring correlations between dual-task performance and biomarkers of neurodegeneration is therefore of interest. Objective: To investigate correlations between Timed Up-and-Go dual-task (TUGdt) outcomes and Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau). Methods: This cross-sectional cohort study included 90 participants (age range …49–84 years) undergoing memory assessment, who were subsequently diagnosed with AD, other dementia disorders, mild cognitive impairment, or subjective cognitive impairment. TUG combined with “Naming Animals” (TUGdt NA) and “Months Backwards” (TUGdt MB), respectively, were used to assess dual-task performance. The number of correct words and time taken to complete the tests were measured. The CSF biomarkers were analysed by ELISA. Spearman’s rank correlation was used for analyses between TUGdt outcomes (TUGdt NA and TUGdt MB), and CSF biomarkers, adjusted for age, gender, and educational level. Results: The number of correct words, as well as the number of correct words/10 s during TUGdt NA correlated negatively to CSF t-tau and p-tau. No correlations were found between any time scores and CSF biomarkers. Conclusion: The correlations between TUGdt NA and t-tau and p-tau may indicate that neurodegeneration affects dual-task performance. Longitudinal studies are needed to further explore dual-task testing in screening for cognitive impairment due to neurodegeneration. Show more

Keywords: Alzheimer’s disease, attention, biomarkers, cerebrospinal fluid, dementia, executive function, gait, mild cognitive impairment, subjective cognitive impairment

DOI: 10.3233/JAD-181265

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019