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

Authors: Fung, Yi Leng | Ng, Kelly E.T. | Vogrin, Simon J. | Meade, Catherine | Ngo, Michael | Collins, Steven J. | Bowden, Stephen C.

Article Type: Research Article

Abstract: Structural neuroimaging is a useful non-invasive biomarker commonly employed to evaluate the integrity of mesial temporal lobe structures that are typically compromised in Alzheimer’s disease. Advances in quantitative neuroimaging have permitted the development of automated segmentation protocols (e.g., FreeSurfer) with significantly increased efficiency compared to earlier manual techniques. While these protocols have been found to be suitable for large-scale, multi-site research studies, we were interested in assessing the practical utility and reliability of automated FreeSurfer protocols compared to manual volumetry on routinely acquired clinical scans. Independent validation studies with newer automated segmentation protocols are scarce. Two FreeSurfer protocols for each …of two regions of interest—the hippocampus and entorhinal cortex—were compared against manual volumetry. High reliability and agreement was found between FreeSurfer and manual hippocampal protocols; however, there was lower reliability and agreement between FreeSurfer and manual entorhinal protocols. Although based on a the relatively small sample of subjects drawn from a memory clinic (n = 27), our study findings suggest further refinements to improve measurement error and most accurately depict true regional brain volumes using automated segmentation protocols are required, especially for non-hippocampal mesial temporal structures, to achieve maximal utility for routine clinical evaluations. Show more

Keywords: Alzheimer’s disease, biomarker, entorhinal cortex, hippocampus, neuroimaging, reproducibility of results, temporal lobe

DOI: 10.3233/JAD-181172

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

Authors: Ameen-Ali, Kamar E. | Simpson, Julie E. | Wharton, Stephen B. | Heath, Paul R. | Sharp, Paul | Brezzo, Gaia | Berwick, Jason

Article Type: Research Article

Abstract: The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer’s disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-β (Aβ). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize …Aβ deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aβ and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression. Show more

Keywords: Alzheimer’s disease, amyloid, astrocytes, hAPP-J20, microglia, recognition memory

DOI: 10.3233/JAD-181238

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

Authors: Becker, Robert E. | Greig, Nigel H.

Article Type: Research Article

Abstract: Neuronal death is the final step in the progression of preclinical Alzheimer’s disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300–400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates’ efficacy against …clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III. Show more

Keywords: Alzheimer’s disease, amyloid hypothesis, animal models, clinical trial failures, neuronal death, programmed cell death, traumatic brain injury

DOI: 10.3233/JAD-181300

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

Authors: Shen, Liang | Ji, Hong-Fang

Article Type: Review Article

Abstract: Developing novel agents for unexplored targets to combat Alzheimer’s disease (AD) represents an urgent task due to its increasing prevalence worldwide. The present paper summarizes the latest studies emerged in the past few years investigating the associations between the “forgotten organ” gut microbiota and AD from the following two aspects: 1) the associations between gut microbiota and AD development by animal models and human studies; and 2) the effects of gut microbiota modulation-based intervention for AD. Then, we propose future perspectives in two promising research areas: 1) developing gut microbiota modulation-based intervention; and 2) developing gut microbiota-associated diagnostic biomarkers for …AD. Knowledge gaps and potential barriers to overcome towards these two goals are also discussed. Show more

Keywords: Alzheimer’s disease, gut microbiota, therapy

DOI: 10.3233/JAD-181143

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

Authors: Hampel, Harald | Vergallo, Andrea | Perry, George | Lista, Simone | the Alzheimer Precision Medicine Initiative (APMI)

Article Type: Review Article

Abstract: Precision medicine (PM) is an evolving scientific renaissance movement implementing key breakthrough technological and scientific advances to overcome the limitations of traditional symptom- and sign-based phenotypic diagnoses and clinical “one-size-fits-all, magic bullet drug development” in these largely heterogeneous target populations. It is a conceptual shift from ineffective treatments for biologically heterogeneous “population averages” to individually-tailored biomarker-guided targeted therapies. PM is defining which therapeutic approach will be the most effective for a specific individual, at a determined disease stage, across multiple medical research fields, including neuroscience, neurology and psychiatry. The launch of the Alzheimer Precision Medicine Initiative (APMI) and its associated …cohort program in 2016—facilitated by the academic core coordinating center run by the Sorbonne University Clinical Research Group in Alzheimer Precision Medicine (Sorbonne University GRC n°21 APM)”—is geared at transforming healthcare, conventional clinical diagnostics, and drug development research in Alzheimer’s disease. Ever since the commencement of the APMI, the international interdisciplinary research network has introduced groundbreaking translational neuroscience programs on the basis of agnostic exploratory genomics, systems biology, and systems neurophysiology applying innovative “big data science”, including breakthrough artificial intelligence-based algorithms. Here, we present the scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the APMI. Show more

Keywords: Alzheimer’s disease, APMI, All of Us Research Program, artificial intelligence, big data, biomarker-guided therapies, precision medicine, systems biology, systems neurophysiology, translational research programs.

DOI: 10.3233/JAD-181121

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

Authors: Umstead, Andrew | Vega, Irving E.

Article Type: Short Communication

Abstract: The accumulation of tau protein aggregates is a pathological hallmark in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the identity of the toxic tau conformation that propagates and induces neurodegeneration is still unknown. Anti-tau antibodies are a common tool used to differentiate between normal and pathological-associated tau forms or as passive immunotherapy in the quest to interfere with tau-mediated neurodegeneration. Here, we show that Tau13, a tau N-terminal antibody, preferentially enriches high molecular weight tau species produced in a tauopathy mouse model and AD. The data suggest that Tau13 has higher affinity to specific tau conformation presence in higher …molecular weight tau species. Show more

Keywords: Aggregation, Alzheimer’s disease, tau, tauopathy

DOI: 10.3233/JAD-181187

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

Authors: Ashford, J. Wesson

Article Type: Article Commentary

Abstract: In this issue, an article by Tiepolt et al. shows that PET scanning using [11 C]PiB can demonstrate both cerebral blood flow (CBF) changes and amyloid-β (Aβ) deposition in patients with mild cognitive dysfunction or mild dementia of Alzheimer’s disease (AD). The CBF changes can be determined because the early scan counts (1–9 minutes) reflect the flow of the radiotracer in the blood passing through the brain, while the Aβ levels are measured by later scan counts (40–70 minutes) after the radiotracer has been cleared from regions to which the radiotracer did not bind. Thus, two different diagnostic measures are …obtained with a single injection. Unexpectedly, the mild patients with Aβ positivity had scan data with only a weak relationship to memory, while the relationships to executive function and language function were relatively strong. This divergence of findings from studies of severely impaired patients highlights the importance of determining how AD pathology affects the brain. A possibility suggested in this commentary is that Aβ deposits occur early in AD and specifically in critical areas of the neocortex affected only later by the neurofibrillary pathology indicating a different role of the amyloid-β protein precursor (AβPP) in the development of those neocortical regions, and a separate component of AD pathology may selectively impact functions of these neocortical regions. The effects of adverse AβPP metabolism in the medial temporal and brainstem regions occur later possibly because of different developmental issues, and the later, different pathology is clearly more cognitively and socially devastating. Show more

Keywords: Alzheimer’s disease, amyloid, cerebral blood flow, cognition, neuroplasticity, pathology

DOI: 10.3233/JAD-181198

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

Authors: Seino, Yusuke | Nakamura, Takumi | Kawarabayashi, Takeshi | Hirohata, Mie | Narita, Sakiko | Wakasaya, Yasuhito | Kaito, Kozue | Ueda, Tetsuya | Harigaya, Yasuo | Shoji, Mikio

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer’s disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40 , Aβ42 , total tau, phosphorylated-tau, and α -synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer’s disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and …Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α -synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α -synuclein levels were increased in ADD/MCI, there was no merit in measuring α -synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40 , Aβ42 , p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases. Show more

Keywords: Aβ40, Aβ42, α-synuclein, cerebrospinal fluid, neurodegenerative diseases, phosphorylated-tau, plasma, total-tau

DOI: 10.3233/JAD-181152

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

Authors: Wang, Xin | Zimmermann, Helena R. | Ma, Tao

Article Type: Review Article

Abstract: Currently there is no cure or effective disease-modifying therapy for Alzheimer’s disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis. Particularly, hyperactive AMPK via phosphorylation has been linked to AD-associated synaptic plasticity impairments, indicating suppression of AMPK activity …might be beneficial for cognitive deficiency in AD. In this review, we will discuss how targeting dysregulation of AMPK signaling could be a feasible therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, AMPK, protein synthesis, signaling transduction, synaptic plasticity

DOI: 10.3233/JAD-181043

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

Authors: Han, Zhijie | Xue, Weiwei | Tao, Lin | Zhu, Feng

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer’s disease (AD) is identified to be significantly regulated by long non-coding RNA (lncRNA) based on in vivo and clinical experiments. Single nucleotide polymorphisms (SNPs) can strongly impact expression and function of lncRNA in AD, and previous genome-wide associations studies (GWAS) have discovered substantial amount of risk SNPs associated with AD. However, current studies omit the important information about SNPs when identifying potential AD-related lncRNAs. In addition to single discovery approach and small-scale samples in these studies, the number of lncRNAs discovered as keys in AD is limited. Here, multiple computational methods were integrated to discover …novel and key lncRNA of the pathology of AD. First, large-scale GWAS data involved in three ethnicities were collected from two authoritative sources, and meta-analyses were conducted to find SNPs significantly associated with AD (tag SNPs). Second, these tag SNPs together with their linkage disequilibrium information were used to discover potential lncRNAs related to AD. Third, after validation by microarray probe re-annotation of 1,282 samples and RNA-seq data analysis of 117 samples, respectively, a total of five key lncRNAs of AD were identified. Finally, possible function of these lncRNAs was predicted by genome mapping, expression quantitative trait loci, differential co-expression, and gene set enrichment analysis. Based on function prediction, four of the five key lncRNAs were identified to affect the risk of AD by regulating corresponding pathogenic genes and pathways, which are involved in regulation of amyloid-β peptide and the immune system. In summary, these findings can facilitate the discovery of potential disease-related lncRNAs and enhance understanding of the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, differential co-expression, genome-wide association study, long non-coding RNA, microarray probe re-annotation

DOI: 10.3233/JAD-181051

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

Authors: Mandal, Pravat K. | Shukla, Deepika | Tripathi, Manjari | Ersland, Lars

Article Type: Editorial

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. The actual cause of AD is still unknown. Oxidative stress is believed to be important player in AD. Glutathione (GSH) is a major antioxidant, and it is already known that GSH is depleted significantly in the hippocampal regions in mild cognitive impairment and AD patients compared to healthy old subjects. Hence there is a serious discussion to improve the brain GSH level by supplementation. This editorial highlights the need for GSH supplementation for the cognitive enhancement in mild cognitive impairment (MCI) and AD.

DOI: 10.3233/JAD-181054

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

Authors: Brugnolo, Andrea | De Carli, Fabrizio | Pagani, Marco | Morbelli, Slivia | Jonsson, Cathrine | Chincarini, Andrea | Frisoni, Giovanni B. | Galluzzi, Samantha | Perneczky, Robert | Drzezga, Alexander | van Berckel, Bart N.M. | Ossenkoppele, Rik | Didic, Mira | Guedj, Eric | Arnaldi, Dario | Massa, Federico | Grazzini, Matteo | Pardini, Matteo | Mecocci, Patrizia | Dottorini, Massimo E. | Bauckneht, Matteo | Sambuceti, Gianmario | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [18 ]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer’s disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer’s Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between …[18 ]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p  < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [18 ]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods. Show more

Keywords: European Alzheimer Disease Consortium, FDG-PET, head-to-head comparison, prodromal Alzheimer’s disease, statistical parametric mapping, volumetric region of interest

DOI: 10.3233/JAD-181022

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

Authors: Marston, Kieran J. | Brown, Belinda M. | Rainey-Smith, Stephanie R. | Peiffer, Jeremiah J.

Article Type: Review Article

Abstract: The global population is aging at an unprecedented rate giving rise to a greater prevalence of age-related illnesses such as dementia and vascular disease. Dementia affects approximately 47 million individuals globally with projections of 130 million by the year 2050. Late-onset Alzheimer’s disease is the most common form of dementia, accounting for approximately 75% of all cases and is characterized by a progressive decline in cognitive function, memory, and cerebral volume. The pathogenesis of Alzheimer’s disease is poorly understood; however, aging, genetics, and an individual’s diet and lifestyle over several decades appear to be key determinants. As there is no …current cure for Alzheimer’s disease, postponing or preventing the onset of Alzheimer’s disease and dementia through therapeutic methods should, therefore, be targeted at individuals decades prior to an individual showing signs or symptoms of decline. As a preventative tool, resistance exercise improves memory, attention, spatial awareness, reaction time, planning, and information processing. Improvements in cognitive performance following resistance exercise and training may be mediated by peripheral elevations in the physiological biomarkers (i.e., neural and vascular) explored in this review. The purpose of this review is to discuss vascular and neuronal degeneration as a cause or consequence of dementia and Alzheimer’s disease, and the biological markers of neurogenesis and blood vessel growth, function, and regulation. We will also explore the merits of acute and chronic resistance training as a strategy to postpone the onset of cognitive decline, dementia, and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive decline, physiology, prevention, resistance training

DOI: 10.3233/JAD-181079

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2019

Authors: Filshtein, Teresa Jenica | Dugger, Brittany N. | Jin, Lee-Way | Olichney, John M. | Farias, Sarah T. | Carvajal-Carmona, Luis | Lott, Paul | Mungas, Dan | Reed, Bruce | Beckett, Laurel A. | DeCarli, Charles

Article Type: Research Article

Abstract: Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 435 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer’s Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer’s disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic …(14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 16 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals. Show more

Keywords: Alzheimer’s disease, autopsy, brain, cognitive aging, cohort studies, dementia, minority groups, neuropathology, vascular

DOI: 10.3233/JAD-180992

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

Authors: Peters, Ruth | Ee, Nicole | Peters, Jean | Booth, Andrew | Mudway, Ian | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia. Objective: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia. Methods: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. …Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299 Results: From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5 ), nitrogen dioxide (NO2 ), nitrous oxides (NOx ), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5 , NO2 /NOx , and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal. Conclusion: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia. Show more

Keywords: Air pollutants, cognitive decline, dementia, particulate matter

DOI: 10.3233/JAD-180631

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

Authors: de la Monte, Suzanne M. | Tong, Ming | Daiello, Lori A. | Ott, Brian R.

Article Type: Research Article

Abstract: Background: Brain insulin resistance is a well-recognized abnormality in Alzheimer’s disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. Objective: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Methods: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and …21 controls using a multiplex ELISA platform. Results: In MCI/AD, both the CSF and serum samples had significantly altered mean levels of C-peptide (both elevated), Visfatin, incretins, PAI-1, ghrelin, and leptin, whereas only CSF showed a significant reduction in insulin and only serum had increased glucagon levels. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. Conclusion: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, insulin resistance, mild cognitive impairment, neurodegeneration, serum

DOI: 10.3233/JAD-180906

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

Authors: Feng, Lei | Cheah, Irwin Kee-Mun | Ng, Maisie Mei-Xi | Li, Jialiang | Chan, Sue Mei | Lim, Su Lin | Mahendran, Rathi | Kua, Ee-Heok | Halliwell, Barry

Article Type: Research Article

Abstract: We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23–0.78, p  = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and its bioactive compounds …in delaying neurodegeneration. Show more

Keywords: Aging, Asians, cross-sectional analysis, mild cognitive impairment, mushrooms

DOI: 10.3233/JAD-180959

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

Authors: Lussier, Maxime | Adam, Stéphane | Chikhaoui, Belkacem | Consel, Charles | Gagnon, Mathieu | Gilbert, Brigitte | Giroux, Sylvain | Guay, Manon | Hudon, Carol | Imbeault, Hélène | Langlois, Francis | Macoir, Joel | Pigot, Hélène | Talbot, Lise | Bier, Nathalie

Article Type: Research Article

Abstract: Background: Functional assessment is of paramount importance when mild cognitive impairment is suspected, but common assessment tools such as questionnaires lack sensitivity. An alternative and innovative approach consists in using sensor technology in smart apartments during scenario-based assessments of instrumental activities of daily living (IADL). However, studies that investigate this approach are scarce and the technology used is not always transposable in healthcare settings. Objective: To explore whether simple and wireless technology used in two different smart environments could add value to performance and rater-based measures of IADL when it comes to predicting mild cognitive impairment (MCI) in …older adults. Methods: Twenty-six (26) cognitively healthy older adults (CH) and 22 older adults with MCI were recruited. Functional performance in a set of five scripted tasks was evaluated with sensor-based observations (motion, contact, and electric sensors) and performance-based measures (rated with videotapes). The five tasks could be performed in any order and were detailed on an instruction sheet given to participants. Results: Sensor-based observations showed that participants with MCI spent more time in the kitchen and looking into the fridge and kitchen cabinets than CH participants. Moreover, these measures were negatively associated with memory and executive performances of participants and significantly contributed to the prediction of MCI. Conclusion: Simple, wireless, and sensor-based technology holds potential for the detection of MCI in older adults as they perform daily tasks. However, some limits are discussed and we offer recommendations to improve the usefulness of this innovative approach. Show more

Keywords: Activities of daily living, memory, mild cognitive impairment, neurocognitive disorders, older adults, smart homes, technology, wireless technology

DOI: 10.3233/JAD-180652

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

Authors: Roda, Alejandro R. | Montoliu-Gaya, Laia | Villegas, Sandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the most common type of dementia worldwide, is characterized by high levels of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Genetically, the ɛ 4 allele of apolipoprotein E (ApoE) has been established as the major risk factor for developing late-onset AD (LOAD), the most common form of the disease. Although the role ApoE plays in AD is still not completely understood, a differential role of its isoforms has long been known. The current review compiles the involvement of ApoE isoforms in amyloid-β protein precursor transcription, Aβ aggregation and clearance, synaptic plasticity, neuroinflammation, lipid metabolism, mitochondrial function, …and tau hyperphosphorylation. Due to the complexity of LOAD, an accurate description of the interdependence among all the related molecular mechanisms involved in the disease is needed for developing successful therapies. Show more

Keywords: Aβ clearance, Aβ aggregation, AβPP transcription, AICD generation, Alzheimer’s disease, amyloid-β, apolipoprotein E, lipid metabolism, mitochondrial damage, neuroinflammation

DOI: 10.3233/JAD-180740

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

Authors: Marjańska, Małgorzata | McCarten, J. Riley | Hodges, James S. | Hemmy, Laura S. | Terpstra, Melissa

Article Type: Research Article

Abstract: This study’s objective was to increase understanding of biological mechanisms underlying clinical Alzheimer’s disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited …from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p  < 0.0007) in both brain regions. Concentrations of the glial marker myo -inositol and the choline-containing compounds involved in membrane turnover were higher (p ≤0.0004) in PCC of participants with AD. Ascorbate and myo -inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo -inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo -inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes. Show more

Keywords: Ascorbate, myo-inositol, neurochemical profile, neuroinflammation, posterior cingulate cortex, ultra-high field, ultra-short echo time

DOI: 10.3233/JAD-180861

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

Authors: McFall, G. Peggy | McDermott, Kirstie L. | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: Non-demented cognitive aging trajectories are characterized by vast level and slope differences and a spectrum of outcomes, including dementia. Objective: The goal of AD risk management (and its corollary, promoting healthy brain aging) is aided by two converging objectives: 1) classifying dynamic distributions of non-demented cognitive trajectories, and 2) identifying modifiable risk-elevating and risk-reducing factors that discriminate stable or normal trajectory patterns from declining or pre-impairment patterns. Method: Using latent class growth analysis we classified three episodic memory aging trajectories for n = 882 older adults (baseline M age=71.6, SD =8.9, range = 53-95, …female=66%): Stable (SMA; above average level, sustained slope), Normal (NMA; average level, moderately declining slope), and Declining (DMA; below average level, substantially declining slope). Using random forest analyses, we simultaneously assessed 17 risk/protective factors from non-modifiable demographic, functional, psychological, and lifestyle domains. Within two age strata (Young-Old, Old-Old), three pairwise prediction analyses identified important discriminating factors. Results: Prediction analyses revealed that different modifiable risk predictors, both shared and unique across age strata, discriminated SMA (i.e., education, depressive symptoms, living status, body mass index, heart rate, social activity) and DMA (i.e., lifestyle activities [cognitive, self-maintenance, social], grip strength, heart rate, gait) groups. Conclusion: Memory trajectory analyses produced empirical classes varying in level and slope. Prediction analyses revealed different predictors of SMA and DMA that also varied by age strata. Precision approaches for promoting healthier memory aging—and delaying memory impairment—may identify modifiable factors that constitute specific targets for intervention in the differential context of age and non-demented trajectory patterns. Show more

Keywords: Biomarkers, dementia prevention, memory trajectories, protective factors, risk factors, Victoria Longitudinal Study

DOI: 10.3233/JAD-180571

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

Authors: Kasahara, Hiroo | Ikeda, Masaki | Nagashima, Kazuaki | Fujita, Yukio | Makioka, Kouki | Tsukagoshi, Setsuki | Yamazaki, Tsuneo | Takai, Eriko | Sanada, Etsuko | Kobayashi, Ayumi | Kishi, Kazuhiro | Suto, Takayuki | Higuchi, Tetsuya | Tsushima, Yoshito | Ikeda, Yoshio

Article Type: Research Article

Abstract: Neuroimages of cerebral amyloid-β (Aβ) accumulation and small vessel disease (SVD) were examined in patients with various types of cognitive disorders using 11 C-labeled Pittsburgh Compound B-positron emission tomography (PiB-PET) and magnetic resonance imaging (MRI). The mean cortical standardized uptake value ratio (mcSUVR) was applied for a quantitative analysis of PiB-PET data. The severity of white matter lesions (WML) and enlarged perivascular spaces (EPVS) on MRI were assessed to evaluate complicating cerebral SVD using semiquantitative scales. In homozygous apolipoprotein E ɛ 3/ɛ 3 carriers, the incidence of more severe WML and EPVS was higher in PiB-positive than PiB-negative patients, indicating …that WML and EPVS might be associated with enhanced Aβ accumulation. An association study between PiB-PET and MRI findings revealed that higher WML grades significantly correlate with lower mcSUVRs, especially in the frontal area, indicating that more severe ischemic MRI findings are associated with milder Aβ accumulation among patients with Alzheimer’s disease. In these patients SVD may accelerate the occurrence of cognitive decline and facilitate early recognition of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, Pittsburgh Compound B, positron emission tomography, white matter lesion

DOI: 10.3233/JAD-180939

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

Authors: Xia, Hui | Wang, Min | Li, Jie-Qiong | Tan, Chen-Chen | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The brain-derived neurotrophic factor (BDNF ) Val66Met polymorphism emerged as a risk factor for Alzheimer’s disease (AD). However, little was known about its effects on the process of potential AD. Objective: To explore the effects of the Val66Met polymorphism on cognition, cerebrospinal fluid (CSF), and neuroimaging markers in non-demented elderly individuals. Methods: A total of 1,081 adults without dementia (375 healthy subjects and 706 individuals with mild cognitive impairment) were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to test the influence of BDNF Val66Met polymorphism on cognitive impairment, brain structure atrophy, and change …in the levels of CSF biomarkers. Moreover, we also conducted our study in abnormal amyloid-β (A +) subgroup and normal amyloid-β (A–) subgroup, as well as in APOE ɛ 4 carriers and non-carriers. Results: The BDNF Val66Met polymorphism had significant association with atrophy of the entorhinal cortex and Mini-Mental State Examination (MMSE) scores in the non-demented elderly and A  + subgroup, while no association was found in A–subgroup. What is more, there was a significant effect of interaction between BDNF Val66Met and amyloid-β load in MMSE. In addition, significant associations of BDNF Val66Met with the entorhinal cortex and ventricular volumes were found among APOE ɛ 4 non-carriers, but not APOE ɛ 4 carriers. Conclusions: The BDNF Val66Met polymorphism is associated with cognitive impairment and brain atrophy among the non-demented elderly, APOE ɛ 4 non-carriers and A  + subgroup, implying the potential of the Val66Met polymorphism as an important genetic factor for AD-related neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β, brain-derived neurotrophic factor, polymorphism

DOI: 10.3233/JAD-180971

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

Authors: Damulina, Anna | Pirpamer, Lukas | Seiler, Stephan | Benke, Thomas | Dal-Bianco, Peter | Ransmayr, Gerhard | Struhal, Walter | Hofer, Edith | Langkammer, Christian | Duering, Marco | Fazekas, Franz | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background/Objective: Higher white matter hyperintensity (WMH) load has been reported in Alzheimer’s disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps. Methods: The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were …assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed. Results: There were no significant between group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p ≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients. Conclusion: In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, periventricular white matter, white matter hyperintensities

DOI: 10.3233/JAD-180982

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

Authors: Taipale, Heidi | Lampela, Pasi | Koponen, Marjaana | Tanskanen, Antti | Tiihonen, Jari | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Antiepileptic drugs (AEDs) have sedative properties which may lead to an increased risk of pneumonia. Objectives: To investigate whether incident AED use is associated with an increased risk of pneumonia among community-dwelling persons with Alzheimer’s disease (AD). In addition, we determined the risk according to duration of AED use and specific AEDs. Methods: Persons with AD were identified from the MEDALZ dataset which includes all community-dwelling persons who received a clinically verified diagnosis of AD during 2005-2011 in Finland (N=70,718). New AED users were identified with one-year washout period. A matched cohort (1 : 1, N=5,769, matching …criteria age, gender, and time since AD diagnoses) of nonusers was formed. Data from nationwide registers included dispensed medications which were modelled with PRE2DUP method, hospitalizations, and causes of death. The association between AED use and hospital admission or death due to pneumonia was analyzed with Cox proportional hazard models. Results: AED use was associated with an increased risk of pneumonia (adjusted HR 1.92, 95% CI 1.63-2.26; incidence rate per 100 person-years 12.58, 95% CI 12.49-12.66 during AED use and 6.41, 95% CI 6.37-6.45 during nonuse). The highest risk was observed during the first month of use (aHR 3.59, 95% CI 2.29-5.61) and the risk remained elevated until two years of use. Of specific drug substances, phenytoin, carbamazepine, valproic acid, and pregabalin were associated with an increased risk. Conclusion: Antiepileptic drug use may increase the risk of pneumonia which is concerning as persons with AD have elevated risk of pneumonia. Show more

Keywords: Alzheimer’s disease, anticonvulsant, antiepileptic, dementia, mood stabilizer, older person, pharmacoepidemiology, pneumonia

DOI: 10.3233/JAD-180912

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

Authors: Rawlings, Andreea M. | Sharrett, A. Richey | Mosley, Thomas H. | Wong, Dean F. | Knopman, David S. | Gottesman, Rebecca F.

Article Type: Short Communication

Abstract: We examined associations between cognitive reserve and late-life amyloid-β deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR) >1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer’s disease pathology on the clinical expression of dementia, rather than by altering …its pathogenesis. Show more

Keywords: Amyloid, cohort study, education, epidemiology, human, PET imaging

DOI: 10.3233/JAD-180785

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

Authors: Nordheim, Johanna | Häusler, Andreas | Yasar, Sevil | Suhr, Ralf | Kuhlmey, Adelheid | Rapp, Michael | Gellert, Paul

Article Type: Research Article

Abstract: Background: Psychosocial interventions may improve the quality of life of both people with dementia (PWD) and their family caregivers. However, research is inconclusive and focused primarily on the quality of life of either the PWD or the caregiver, rather than on both. Objective: Our aim was to evaluate the effect of couple-based interdisciplinary psychosocial intervention in patients with mild-to-moderate dementia on quality of life of both partners. Methods: 108 community-dwelling PWD and their caregiving partners were enrolled in this pragmatic randomized controlled trial. The intervention consisted of 7 sessions at participants’ homes led by a psychotherapist …and a social worker. Quality of life was evaluated at baseline, one, and six-month follow-up for patients and their partners. Mixed effects models have been applied. Results: Intervention allocation was not associated with an improvement in quality of life in either the patients or their partners. In subgroup analyses, intervention was negatively associated with caregiver performance. However, this was only present in those reporting poor relationship quality. Patients in the intervention group who reported good relationship quality were found to have decreased cognitive decline. Conclusion: A couple-based interdisciplinary intervention did not yield improvements in quality of life. This may be the result of a bias caused by an increased awareness due to the intervention. Relationship quality and support in the long-term should be considered when designing and implementing interventions for PWD and their partners. Show more

Keywords: Caregiving, coping with illness/disability, dementia, family, psychosocial intervention, quality of life

DOI: 10.3233/JAD-180812

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

Authors: DeCarli, Charles | Villeneuve, Sylvia | Maillard, Pauline | Harvey, Danielle | Singh, Baljeet | Carmichael, Owen | Fletcher, Evan | Olichney, John | Farias, Sarah | Jagust, William | Reed, Bruce | Mungas, Dan

Article Type: Research Article

Abstract: Background/Objective: To determine the impact of vascular burden on rates of decline in episodic memory and executive function. We hypothesize that greater vascular burden will have an additive negative impact on cognition after accounting for baseline cognitive impairment, positron emission tomography (PET) amyloid burden, and magnetic resonance imaging (MRI) measures. Methods: Individuals were followed an average of 5 years with serial cognitive assessments. Predictor variables include vascular burden score (VBS), quantitative brain MRI assessment, and amyloid imaging. Subjects consisted of 65 individuals, 53% of whom were male, aged 73.2±7.2 years on average with an average of 15.5±3.3 years …of educational achievement. Results: Baseline cognitive impairment was significantly associated poorer episodic memory (p  < 0.0001), smaller hippocampal volume (p  < 0.0001), smaller brain volume (p  = 0.0026), and greater global Pittsburg Imaging Compound B (PiB) index (p  = 0.0008). Greater amyloid burden was associated with greater decline in episodic memory over time (β= –0.20±0.07, p  < 0.005). VBS was significantly associated with the level of executive function performance (β= –0.14±0.05, p  < 0.005) and there was a significant negative interaction between VBS, cognitive impairment, and PiB index (β= –0.065±0.03, p  = 0.03). Conclusions: Our results find a significant influence of VBS independent of standard MRI measures and cerebral amyloid burden on executive function. In addition, VBS reduced the amount of cerebral amyloid burden needed to result in cognitive impairment. We conclude that the systemic effects of vascular disease as reflected by the VBS independently influence cognitive ability. Show more

Keywords: Alzheimer’s disease, cerebrovascular disorders, cognition, neuroimaging

DOI: 10.3233/JAD-180965

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

Authors: Byman, Elin | Schultz, Nina | the Netherlands Brain Bank | Blom, Anna M. | Wennström, Malin

Article Type: Research Article

Abstract: Background: Astrocytes produce and store the energy reserve glycogen. However, abnormal large glycogen units accumulate if the production or degradation of glycogen is disturbed, a finding often seen in patients with Alzheimer’s disease (AD). We have shown increased activity of glycogen degrading α -amylase in AD patients and α -amylase positive glial cells adjacent to AD characteristic amyloid-β (Aβ) plaques. Objectives: Investigate the role of α -amylase in astrocytic glycogenolysis in presence of Aβ. Methods: Presence of α -amylase and large glycogen units in postmortem entorhinal cortex from AD patients and non-demented controls were analyzed by …immunohistological stainings. Impact of different Aβ42 aggregation forms on enzymatic activity (α -amylase, pyruvate kinase, and lactate dehydrogenase), lactate secretion, and accumulation of large glycogen units in cultured astrocytes were analyzed by activity assays, ELISA, and immunocytochemistry, respectively. Results: AD patients showed increased number of α -amylase positive glial cells. The glial cells co-expressed the astrocytic marker glial fibrillary acidic protein, displayed hypertrophic features, and increased amount of large glycogen units. We further found increased load of large glycogen units, α -amylase immunoreactivity and α -amylase activity in cultured astrocytes stimulated with fibril Aβ42 , with increased pyruvate kinase activity, but unaltered lactate release as downstream events. The fibril Aβ42 -induced α -amylase activity was attenuated by β-adrenergic receptor antagonist propranolol. Discussion: We hypothesize that astrocytes respond to fibril Aβ42 in Aβ plaques by increasing their α -amylase production to either liberate energy or regulate functions needed in reactive processes. These findings indicate α -amylase as an important actor involved in AD associated neuroinflammation. Show more

Keywords: α-amylase, Alzheimer’s disease, amyloid-β, astrocytes, glycogenolysis

DOI: 10.3233/JAD-180997

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

Authors: Devanarayan, Priya | Devanarayan, Viswanath | Llano, Daniel A. | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and neurodegeneration (ATN) for diagnosis and staging of Alzheimer’s disease (AD). Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3–10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ42 , total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also …measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework. Show more

Keywords: Biomarker, mild cognitive impairment, PTPRN, receptor-type tyrosine-phosphatase-like N

DOI: 10.3233/JAD-180905

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

Authors: Conner, Sarah C. | Benayoun, Laurent | Himali, Jayandra J. | Adams, Stephanie L. | Yang, Qiong | DeCarli, Charles | Blusztajn, Jan K. | Beiser, Alexa | Seshadri, Sudha | Delalle, Ivana

Article Type: Research Article

Abstract: Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer’s disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502 , G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, …dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998–2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoprotein ɛ 4 allele (APOE4 ), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4 . Show more

Keywords: Framingham Heart Study, hippocampus, MSRB3 , vascular pathology

DOI: 10.3233/JAD-180977

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

Authors: Griffith, Chelsea M. | Macklin, Lauren N. | Cai, Yan | Sharp, Andrew A. | Yan, Xiao-Xin | Reagan, Lawrence P. | Strader, April D. | Rose, Gregory M. | Patrylo, Peter R.

Article Type: Research Article

Abstract: Several studies have demonstrated that mouse models of Alzheimer’s disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1–3 months and 6–8 months old) and post-pathology (16–18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. …Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD. Show more

Keywords: 3xTg-AD, AKT, Alzheimer’s disease, diabetes, glucose, GLUT, hippocampus, insulin, metabolism

DOI: 10.3233/JAD-180707

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-29, 2019

Authors: Guo, Jing | Xu, Cheng | Ni, Shaozhou | Zhang, Shujuan | Li, Qihang | Zeng, Peng | Pi, Guilin | Liu, Enjie | Sun, Dong-Sheng | Liu, Yanchao | Wang, Zhouyi | Chen, Haote | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Hyperhomocysteinemia is an independent risk factor of Alzheimer’s disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of …hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage. Show more

Keywords: Alzheimer’s disease, hyperhomocysteinemia, methylated/de-methylated protein phosphatase-2A, phosphorylated tau, retina

DOI: 10.3233/JAD-180978

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

Authors: Depciuch, Joanna | Zawlik, Izabela | Skrzypa, Marzena | Pająk, Justyna | Potocka, Natalia | Łach, Kornelia | Bartosik-Psujek, Halina | Koziorowska, Anna | Kaznowska, Ewa | Cebulski, Józef

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a disease of advanced civilization and a common form of dementia in people over 65 years of age. We used Fourier transform infrared (FTIR) spectroscopy combined with principal component analysis (PCA) to determine changes in the quantity and quality of the cerebrospinal fluid from AD patients at three different stages of the disease (ADI, ADII, and ADIII), as well as from patients with mild cognitive impairment (MCI). Moreover, based on the FTIR spectra, we calculated the ratio of α -helix and β-sheet secondary protein structures as well as the lipid-protein balance as potential AD markers. The …FTIR spectra of cerebrospinal fluid obtained from MCI, ADI, ADII, and ADIII patients showed that peaks corresponding to protein and deoxyribonucleic acid (DNA), and phospholipid and lipid vibrations were shifted in comparison with those of control subjects. Furthermore, the levels of these chemical compounds were lower in the patients than in the control subjects. The β-sheet secondary protein structure levels were increased in the MCI and AD patients compared with the control subjects. In addition, significant changes in the lipid-protein balance were observed. Interestingly, as the disease progressed, the lipid-protein balance became further disrupted, that is, the lipid amount decreased with disease progression. PCA analysis of lipid-protein FTIR regions revealed that the spectra could be used to distinguish between controls and patients with MCI, ADI, ADII, and ADIII. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, Fourier transform infrared spectroscopy, lipid-protein balance, PCA-LDA

DOI: 10.3233/JAD-181008

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

Authors: Bocai, Nadia I. | Marcora, María S. | Belfiori-Carrasco, Lautaro F. | Morelli, Laura | Castaño, Eduardo M.

Article Type: Review Article

Abstract: The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and …analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases. Show more

Keywords: Dementia, endoplasmic reticulum stress, tau proteins, tauopathies, unfolded protein response

DOI: 10.3233/JAD-181021

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2019

Authors: Giil , Lasse Melvaer | Solvang, Stein-Erik Hafstad | Giil, Malin Melvaer | Hellton, Kristoffer H. | Skogseth, Ragnhild Eide | Vik-Mo, Audun Osland | Hortobágyi, Tibor | Aarsland, Dag | Nordrehaug, Jan Erik

Article Type: Research Article

Abstract: Background: Epidemiological studies link serum potassium (K + ) to cognitive performance, but whether cognitive prognosis in dementia is related to K + levels is unknown. Objective: To determine if K + levels predict cognitive prognosis in dementia and if this varies according to diagnosis or neuropathological findings. Methods: This longitudinal cohort study recruited 183 patients with mild Alzheimer’s disease or Lewy body dementia (LBD). Serum K + and eGFR were measured at baseline and medications which could affect K + registered. The Mini-Mental State Examination (MMSE) was measured annually over 5 years, and mortality registered. Association …between K + and √(30 -MMSE) was estimated overall, and according to diagnosis (joint model). Associations between MMSE-decline and K + were assessed in two subgroups with neuropathological examination (linear regression) or repeated measurements of K + over 3 years (mixed model). Results: Serum K + at baseline was associated with more errors on MMSE over time (Estimate 0.18, p  = 0.003), more so in LBD (p  = 0.048). The overall association and LBD interaction were only significant in the 122 patients not using K + relevant medication. Repeated K + measures indicated that the association with MMSE errors over time was due to a between-person effect (p  <  0.05, n  = 57). The association between the annual MMSE decline was stronger in patients with autopsy confirmed LBD and more α -synuclein pathology (all: p  <  0.05, n  = 41). Conclusion: Higher serum K + predicts poorer cognitive prognosis in demented patients not using medications which affect K + , likely a between-person effect seen mainly in LBD. Show more

Keywords: α-synuclein, Alzheimer’s disease, cognitive decline, kalium, Lewy body dementia, Mini-Mental State Examination, MMSE-decline, potassium

DOI: 10.3233/JAD-181131

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Fujikura, Mai | Iwahara, Naotoshi | Hisahara, Shin | Kawamata, Jun | Matsumura, Akihiro | Yokokawa, Kazuki | Saito, Taro | Manabe, Tatsuo | Matsushita, Takashi | Suzuki, Syuuichirou | Shimohama, Shun

Article Type: Research Article

Abstract: We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ ) in Alzheimer’s disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ 1 - 42 (fAβ 42 …) phagocytosis in microglia. CD14 has also been known to control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ 42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ 42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ 42 , showing their involvement in fAβ 42 uptake. We also found that clathrin participated in fAβ 42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ 42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ 42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ 42 uptake, which could be of therapeutic relevance for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , CD14, clathrin, microglia, Toll-like receptor 4

DOI: 10.3233/JAD-180904

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

Authors: Groeneveld, Onno N. | Moneti, Costanza | Heinen, Rutger | de Bresser, Jeroen | Kuijf, Hugo J. | Exalto, Lieza G. | Boomsma, Jooske M.F. | Kappelle, L.Jaap | Barkhof, Frederik | Prins, Niels D. | Scheltens, Philip | van der Flier, Wiesje M. | Biessels, Geert Jan | and on behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer’s disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n  = 147, 68.4±7.9 years, 63% men; …no T2DM: n  = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer’s disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p  <  0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: – 0.17, p  = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥ Show more

Keywords: Cerebrospinal fluid, magnetic resonance imaging, prognosis, type 2 diabetes mellitus, vascular brain injury

DOI: 10.3233/JAD-180914

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

Authors: Onojighofia Tobore, Tobore

Article Type: Research Article

Abstract: Alzheimers’ disease (AD) is the most common cause of dementia, with an estimated 5 million new cases occurring annually. Among the elderly, AD shortens life expectancy, results in disability, decreases quality of life, and ultimately, leads to institutionalization. Despite extensive research in the last few decades, its heterogeneous pathophysiology and etiopathogenesis have made it difficult to develop an effective treatment and prevention strategy. Aging is the biggest risk factor for AD and evidence suggest that the total number of older people in the population is going to increase astronomically in the next decades. Also, there is evidence that air pollution …may result in higher incidence and prevalence of AD. This makes the need for a comprehensive understanding of the etiopathogenesis and pathophysiology of the disease extremely critical. In this paper, a quintuple framework of thyroid dysfunction, vitamin D deficiency, sex hormones, and mitochondria dysfunction and oxidative stress are used to provide a comprehensive description of AD etiopathogenesis and pathophysiology. The individual role of each factor, their synergistic and genetic interactions, as well as the limitations of the framework are discussed. Show more

Keywords: Alzheimer’s disease, amyloid-β , dementia, hyperphosphorylated tau, melatonin, mitochondria dysfunction, oxidative stress, pathogenesis, sex hormones, thyroid hormone, vitamin D

DOI: 10.3233/JAD-181052

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2018

Authors: Li, Hong | Leurgans, Sue | Elm, Jordan | Gebregziabher, Mulugeta

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a common, devastating disease which carries a heavy economic burden. Accelerated efforts to identify presymptomatic stages of AD and biomarkers to classify the disease are urgent needs. Currently no biomarkers can perfectly discriminate individuals into multiple disease categories of AD (no cognitive impairment, mild cognitive impairment, and dementia). Although many biomarkers for diagnosis and their various features are being studied, we lack advanced statistical methods which can fully utilize biomarkers to classify AD accurately, thereby facilitating evaluation of putative markers both alone and in combination. In this paper, we propose two approaches: 1) a forward addition …procedure in which we adapt an additive logistic regression model to the setting for disease with ordered multiple categories. Using this approach, we select and combine multiple cross-sectional biomarkers to improve diagnostic accuracy, and 2) a method by extending the Neyman-Pearson Lemma to the ordered three disease categories to construct optimal cutoff points to distinguish multiple disease categories. We evaluate the robustness of the proposed model using a simulation study. Then we apply these two methods to data from the Religious Orders Study to examine the feasibility of combining biomarkers, and compare the diagnostic accuracy between the proposed methods and existing methods including model-based methods (ordinal logistic regression and quadratic discriminant analysis), a tree-based method CART, and the Youden index method. The two proposed methods facilitate evaluations of biomarkers for conditions with graded, rather than binary, classifications. The evaluation of the performance of different approaches provides guidance of how to choose approaches to address research questions. Show more

Keywords: Alzheimer’s disease, diagnostic accuracy, generalized additive model, multiclass classification, optimal cutoff point, volume under the surface

DOI: 10.3233/JAD-180580

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

Authors: Cedres, Nira | Machado, Alejandra | Molina, Yaiza | Diaz-Galvan, Patricia | Hernández-Cabrera, Juan Andres | Barroso, Jose | Westman, Eric | Ferreira, Daniel

Article Type: Research Article

Abstract: Subjective cognitive complaints in cognitively normal individuals are a relevant predictor of Alzheimer’s disease (AD), cerebrovascular disease, and age-related tauopathy. Complaints starting after the age of 60 increase the likelihood of preclinical AD. However, this criterion is arbitrary and current data show that neurodegenerative disorders likely start before that age. Further, data on the role of subjective complaints below the age of 60 in individuals qualifying for subjective cognitive decline (SCD) are lacking. We investigated the association of subjective cognitive complaints with an extensive number of neuroimaging, demographic, clinical, and cognitive measures in individuals fulfilling criteria for SCD below and …above the age of 60. Nine complaints were scored in 416 individuals. Complaints were related to a higher load of white matter signal abnormalities, and this association was stronger the more subclinical changes in personality, interest, and drive were reported. In individuals <60 years, complaints were associated with lower global cognitive performance. In individuals ≥60 years, complaints were related to greater global brain atrophy and smaller total intracranial volume, and this association was stronger the more subclinical difficulties in activities of daily living were reported. Also, complaints were associated with increased depressive symptomatology irrespective of age. We conclude that complaints below the age of 60 may be associated with subtle signs of brain pathology. In the community, screening for risk of future cognitive decline should include subjective cognitive complaints, depressive symptomatology, and subclinical reduced cognition (<60 years)/activities of daily living (≥60 years), supported by basic neuroimaging examinations. Show more

Keywords: Brain atrophy, depressive symptomatology, middle-age, multivariateanalysis, subjective cognitive decline, white matter signal abnormalities

DOI: 10.3233/JAD-180720

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

Authors: Manniche, Christina Strand-Holm | Hejl, Anne-Mette | Hasselbalch, Steen Gregers | Simonsen, Anja H.

Article Type: Research Article

Abstract: Background: The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. Objective: To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD). Methods: A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: “Cerebrospinal fluid”, “diagnos*”, “hydrocephalus, normal …pressure”. Relevant data were extracted to assess the risk of bias in the included studies. Results: Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ 42 ), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ 42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. Conclusion: T-tau and p-tau may differentiate iNPH from AD and Aβ 42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, normal pressure hydrocephalus, vascular dementia

DOI: 10.3233/JAD-180816

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

Authors: Li, Li | Zhen, Eugene Y. | Decker, Rodney L. | Willis, Brian A. | Waters, David | Liu, Peng | Hake, Ann Marie | Demattos, Ronald Bradley | Ayan-Oshodi, Mosun

Article Type: Research Article

Abstract: LY2599666 is a humanized, affinity-optimized monoclonal antibody antigen-binding fragment linked to a PEG molecule and targets soluble amyloid-β (Aβ) monomers. This first-in-human dose ascending study assessed pharmacokinetics (PK) (measured as serum free LY2599666 concentration) and pharmacodynamic (PD) effects (measured as plasma total soluble Aβ 40 and Aβ 42 ) after a single subcutaneous (SC) dose of 10, 25, 100, and 200 mg LY2599666 in healthy subjects. As LY2599666 binds to multiple soluble Aβ monomers, a two-target mediated drug disposition model (TMDD) was developed to simultaneously fit serum LY2599666 concentration and Aβ monomer levels. Four Alzheimer’s disease patients completed 25 mg once-weekly …dosing of LY2599666 for 12 weeks. In addition, single cerebrospinal fluid samples were collected to assess penetration capability across the blood-brain barrier. PK and PD data collected from the multiple dose cohort aligned with model predictions, suggesting the established TMDD model predicted suppression of soluble Aβ 40 and Aβ 42 in plasma after SC dosing of LY2599666. Show more

Keywords: Aβ monomer, Alzheimer’s disease, pharmacokinetic/pharmacodynamic, target-mediated drug disposition

DOI: 10.3233/JAD-180925

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

Authors: Dao, Elizabeth | Hsiung, Ging-Yuek Robin | Sossi, Vesna | Tam, Roger | Shahinfard, Elham | Nicklin, Eloise | Al Keridy, Walid | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Impaired physical function (i.e., slowing of gait, muscle weakness, and poor mobility) is common in older adults with cognitive impairment and dementia. Evidence suggests that cerebral small vessel disease, specifically white matter lesions (WMLs), is associated with impaired physical function, but little research has been conducted to understand the specific role of AD pathology in physical outcomes. Objective: The objective of this study was to examine the association between cerebral amyloid-β (Aβ ) deposition and physical function in people with cognitive impairment. Methods: Thirty participants completed an 11 C Pittsburgh compound B (PIB) position …emission tomography (PET) scan to quantify global Aβ deposition using standardized uptake value ratio (SUVR). We assessed usual gait speed, muscle strength of the lower extremities, balance, and functional mobility using the Short Physical Performance Battery (SPPB) and the Timed Up and Go Test (TUGT). Multiple linear regression analyses examined the association between Aβ and each measure of physical function, adjusting for age, body mass index, and WML load. Results: Global PIB SUVR was significantly associated with usual gait speed (β = –0.52, p  = 0.01) and SPPB performance (β = –0.47, p  = 0.02), such that increased Aβ deposition was associated with reduced performance on both measures. Global PIB SUVR was not significantly associated with TUGT performance (β = 0.32, p  = 0.08). Conclusions: Cerebral Aβ deposition is associated with reduced gait speed, muscle strength, and balance in older adults with cognitive impairment independent of WML load. However, Aβ deposition was not associated with functional mobility. Show more

Keywords: Alzheimer’s disease, amyloid-β , mild cognitive impairment, mobility, physical function

DOI: 10.3233/JAD-180848

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

Authors: Li, Lexiao | Ismael, Saifudeen | Nasoohi, Sanaz | Sakata, Kazuko | Liao, Francesca-Fang | McDonald, Michael P. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques and …compared with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β ) were co-localized near Aβ plaques and tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β , the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias. Show more

Keywords: Alzheimer’s disease, amyloid plaques, hyperphosphorylated tau, NLRP3 inflammasome interlukin-1, thioredoxin-interacting protein

DOI: 10.3233/JAD-180814

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Takamatsu, Yoshiki | Ho, Gilbert | Waragai, Masaaki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon …to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution. Show more

Keywords: Alzheimer’s disease, amyloid-β , antagonistic pleiotropy, disease-modifying therapy, evolvability, natural selection, schizophrenia, transgenerational

DOI: 10.3233/JAD-180986

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Jacob, Louis | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Previous research has found a positive association between the use of antiepileptic drugs (AEDs) and dementia. However, there have been some concerns about the generalizability of its findings. Objective: The goal of this case-control study was to analyze the association between AED use and dementia risk in Germany. Methods: This study included patients who had received a first dementia diagnosis from one of 1,203 general practitioners or 202 neuropsychiatrists between 2013 and 2017 (index date). Controls without dementia were matched (1:1) to dementia cases by age, gender, physician, diagnosis of mild cognitive …impairment, and observation time prior to the index date. Two regression models were used to analyze the association between AED use and dementia risk after adjusting for comorbidities and co-prescribed drugs. AEDs were included as a dichotomous variable in Model 1 (ever versus never use) and as a continuous variable in Model 2 (duration of treatment in years). Results: A total of 50,575 cases with dementia and 50,575 controls without dementia were included in this study. Model 1 (odds-ratio [OR] = 0.99) and Model 2 (OR = 1.00) showed no significant association between AED use and dementia risk. However, prescriptions for levetiracetam generic brands (Model 1: OR = 1.70; Model 2: OR = 1.36) were associated with an increased dementia risk. Conclusions: Overall, AED use was not significantly associated with dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany between 2013 and 2017. Nonetheless, the potential deleterious effects of levetiracetam generic brands on cognition deserve further investigation. Show more

Keywords: Antiepileptic drug, case-control study, dementia, Germany, risk factor

DOI: 10.3233/JAD-181194

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Marwarha, Gurdeep | Claycombe-Larson, Kate | Lund, Jonah | Schommer, Jared | Ghribi, Othman

Article Type: Research Article

Abstract: Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer’s disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months …and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κ B transcriptional activity resulting in NF-κ B-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κ B activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1, linoleate, NF-κB, oxidative stress, palmitate

DOI: 10.3233/JAD-180835

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2018

Authors: Cherbuin, Nicolas | Walsh, Erin I. | Prina, A. Matthew

Article Type: Research Article

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is a major disease burden which accounts for 5% of all deaths globally, with most of those (>90%) occurring in lower to middle income countries (LMIC). It is also emerging as an important modifiable dementia risk factor. Objective: To address the knowledge gap surrounding the nature of the associations between COPD, dementia, and mortality, and the geographical variation of those associations in LMIC. Methods: Data from the 10/66 study surveying 15,394 participants (mean age 74 years, 62% female) across 8 countries was used to estimate the prevalence of self-reported COPD …and its association with incident dementia and premature death. Proportional sub-hazards models using a cumulative incidence function were applied to identify the probability of incident dementia onset given the risk of premature death, with estimates pooled across countries via random effect meta-analysis. Results: Over the 3-year follow-up, almost 10% of participants developed dementia and 14% were deceased. COPD was not significantly associated with dementia incidence except in Cuba. However, fully adjusted models indicated that individuals with COPD were at a 28% increased risk of premature death, a trend present across most countries when analyzed individually. Conclusion: The link between COPD and dementia is currently somewhat different and weaker in LMIC than in developed countries. This may be because premature death in the populations studied mask the development of clinical dementia. Given the global trend toward increased life expectancy, it is critical that the disease burden associated with COPD be addressed without delay if a further rise in dementia prevalence associated with COPD is to be avoided in LMIC. Show more

Keywords: Chronic obstructive pulmonary disease, lower to middle income countries, mild cognitive impairment, premature death, prevalence

DOI: 10.3233/JAD-180562

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Danat, Isaac M. | Clifford, Angela | Partridge, Martin | Zhou, Weiju | Bakre, Aishat T. | Chen, Anthony | McFeeters, Danielle | Smith, Tina | Wan, Yuhui | Copeland, John | Anstey, Kaarin J. | Chen, Ruoling

Article Type: Research Article

Abstract: Background: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia. Objective: To assess the impacts of overweight and obesity in older age on incident dementia. Methods: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference …(WC). Results: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data was 0.97 (95% CI 0.95–1.00); in those with followed up <9 years was 0.95 (0.93–0.96) while in ≥9 years follow-up was 1.03 (0.96–1.11). In five studied populations examining categorical BMI, RR of dementia in older people classified as overweight and obese was 0.98 (0.54–1.77) and 1.17 (0.65–2.10) respectively, in comparison with other weights. The pooled WC data showed no association between increased WC and reduced risk of dementia. Conclusion: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk. Show more

Keywords: Body weight, dementia, meta-analysis, older people

DOI: 10.3233/JAD-180763

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018