Journal of Alzheimer's Disease - Volume 53, issue 1

Authors: van de Vorst, Irene E. | Koek, Huiberdina L. | Bots, Michiel L. | Vaartjes, Ilonca

Article Type: Research Article

Abstract: Background: Insight in causes of death in demented patients may help physicians in end-of-life care. Objectives: To investigate underlying causes of death (UCD) in demented patients stratified by age, sex, dementia subtype [Alzheimer’s disease (AD), vascular dementia (VaD)] and to compare them with UCD in the general population (GP). Methods: A nationwide cohort of 59,201 patients with dementia (admitted to a hospital or visiting a day clinic) was constructed [38.7% men, 81.4 years (SD 7.0)] from 2000 through 2010. UCDs were reported and compared to the GP by calculating relative risks (RRs). Results: …During follow up [median follow up time 1.3 years (IQR 0.3– 3.0)], 64.2% of women and 69.3% of men died. Leading UCDs were dementia (17.5% in men and 23.7% in women) and cardiovascular disease (CVD) (18.7% and 19.2%, respectively). When compared to the GP, dementia was a more common UCD (RR in men 4.65, 95% CI 4.43–4.88), while CVD (RR in men 0.67, 95% CI 0.65–0.68) and cancer (RR 0.40, 95% CI 0.39–0.41) were less common. These differences were more pronounced in patients aged between 60–69 as compared to those aged≥90 years. Patients with AD died less often of cerebrovascular diseases as compared to VaD (RR in men 0.53, 95% CI 0.47–0.59). Conclusion: UCDs in patients with dementia differs from that of the GP, as dementia is more often and cancer less often an UCD. Although less frequent compared to the GP, CVD also is one of the leading UCDs in patients with dementia. This information is valuable for targeted advance care planning. Show more

Keywords: Cardiovascular disease, cause of death, cohort, dementia, mortality

DOI: 10.3233/JAD-150925

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 117-125, 2016

Authors: Uekawa, Ken | Hasegawa, Yu | Senju, Satoru | Nakagata, Naomi | Ma, Mingjie | Nakagawa, Takashi | Koibuchi, Nobutaka | Kim-Mitsuyama, Shokei

Article Type: Research Article

Abstract: This work was performed to test our hypothesis that angiotensin-(1–7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer’s disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1–7), or (3) angiotensin-(1–7)+A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1–7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1–7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1–7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer’s disease.

Keywords: Acetazolamide, angiotensin-(1–7), cognitive function, Mas receptor, vascular reactivity, water maze test

DOI: 10.3233/JAD-150642

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 127-133, 2016

Authors: Staekenborg, Salka S. | Pijnenburg, Yolande A.L. | Lemstra, Afina W. | Scheltens, Philip | vd Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months. Objective: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death. Methods: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis (‘non-rapid mortality’). Results: We included …129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29%  <65 y], 70[55%]M, MMSE 20±5). Mean(SD) survival was 12±7 months. Compared to non-rapid mortality patients (n  = 892; age 68±9, 503(56%)M, MMSE 22±5), patients with rapid mortality were slightly older at time of diagnosis, had lower MMSE scores, more depressive symptoms and higher prevalence of a cardiovascular history (all p  < 0.05). Alzheimer’s disease (AD, 43%) was most frequent in patients with rapid mortality, but the occurrence was much lower compared to non-rapid mortality patients (71%), while all other dementia diagnoses, especially Creutzfeldt-Jakob disease (CJD), vascular dementia (VaD), and frontotemporal dementia (FTD), were more frequent (p  < 0.001). There were no specific characteristics for AD patients with rapid versus non-rapid mortality, especially APOE genotypes and CSF-profiles were comparable (p  > 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD. Conclusions: Short survival is relatively common (∼13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD. Show more

Keywords: Dementia, mortality, rapid progression

DOI: 10.3233/JAD-151063

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 135-142, 2016

Authors: Tsai, Chia-Liang | Pai, Ming-Chyi | Ukropec, Jozef | Ukropcová, Barbara

Article Type: Research Article

Abstract: Although elderly people with amnestic mild cognitive impairment (aMCI) have been found to show impaired behavioral performance in task switching, no research has yet explored the electrophysiological mechanisms and the potential correlation between physical fitness and neurocognitive (i.e., behavioral and electrophysiological) performance in aMCI. The present study was thus aimed to examine whether there are differences in electrophysiological (i.e., event-related potential) performance between aMCI participants and controls when performing a task-switching paradigm, and to investigate the role of physical fitness in the relationship between neurocognitive performance and aMCI. Sixty participants were classified into aMCI (n  = 30) and control (n  = 30) …groups, and performed a task-switching paradigm with concomitant electrophysiological recording, as well as underwent senior functional physical fitness tests. The aMCI group showed comparable scores on most parts of the physical fitness tests, but reduced lower body flexibility and VO2max as compared to the control group. When performing the task-switching paradigm, the aMCI group showed slower reaction times in the heterogeneous condition and larger global switching costs, although no significant difference was observed in accuracy rates between the two groups. In addition, the aMCI group showed significantly prolonged P3 latencies in the homogeneous and heterogeneous conditions, and a smaller P3 amplitude only in the heterogeneous condition. The level of cardiorespiratory fitness was significantly correlated with P3 amplitude in the aMCI group, particularly in the heterogeneous condition of the task-switching paradigm. These results show that the aMCI group exhibited abnormalities in their neurocognitive performance when performing the task-switching paradigm and such a deficit was likely associated with reduced cardiorespiratory fitness, which was shown to be the important predictor of neurocognitive performance. Show more

Keywords: Alzheimer’s disease, executive control, mild cognitive impairment, physical fitness, task switching

DOI: 10.3233/JAD-151093

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 143-159, 2016

Authors: Vidoni, Eric D. | Watts, Amber S. | Burns, Jeffrey M. | Greer, Colby S. | Graves, Rasinio S. | Van Sciver, Angela | Black, Jessica R. | Cooper, Sarah K. | Nagely, Allison C. | Uphoff, Elaine | Volmer, Jennifer M. | Bieberle, Natalie A.

Article Type: Research Article

Abstract: Background: Effective programs for promoting physical activity are needed for those with cognitive impairment. Objective: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic. Methods: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort …an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test. Results: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort. Conclusions: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners. Show more

Keywords: Alzheimer’s disease, clinic activities, exercise, mobile health

DOI: 10.3233/JAD-160158

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 161-170, 2016

Authors: Happich, Michael | Kirson, Noam Y. | Desai, Urvi | King, Sarah | Birnbaum, Howard G. | Reed, Catherine | Belger, Mark | Lenox-Smith, Alan | Price, David

Article Type: Research Article

Abstract: Background: Prior diagnosis of Alzheimer’s disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis. Objective: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK. Methods: Patients with a final VaD diagnosis, continuous data visibility for≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to …similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis. Results: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately GBP2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter. Conclusion : Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD. Show more

Keywords: Alzheimer’s disease, cost and cost analysis, diagnosis, health resources, vascular dementia

DOI: 10.3233/JAD-150685

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 171-183, 2016

Authors: Zhang, Junying | Liu, Zhen | Li, Zixiao | Wang, Yunxia | Chen, Yaojing | Li, Xin | Chen, Kewei | Shu, Ni | Zhang, Zhanjun

Article Type: Research Article

Abstract: Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that …type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, graph theory, type 2 diabetes mellitus, white matter network

DOI: 10.3233/JAD-160111

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 185-195, 2016

Authors: Peters, Christian | Sepúlveda, Fernando J. | Fernández-Pérez, Eduardo J. | Peoples, Robert W. | Aguayo, Luis G.

Article Type: Research Article

Abstract: Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA …approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia. Show more

Keywords: Alzheimer’s disease, amyloid-beta, glutamate, glycine receptor, hippocampal neurons, membrane damage, membrane pore, NMDA receptor

DOI: 10.3233/JAD-160170

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 197-207, 2016

Authors: Farnsworth, Bryn | Peuckert, Christiane | Zimmermann, Bettina | Jazin, Elena | Kettunen, Petronella | Emilsson, Lina Sors

Article Type: Research Article

Abstract: Quaking (QKI ) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5 , QKI6 , and QKI7 ) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP , PSEN1 , PSEN2 , and MAPT , were also investigated. A real-time PCR assay of …123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI , QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP , PSEN1 , PSEN2 , and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP , PSEN1 , PSEN2 , and MAPT , and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered. Show more

Keywords: Amyloid-β, APP, gene expression, glia, MAPT, neurodegenerative diseases, real-time polymerase chain reaction, PSEN1, PSEN2

DOI: 10.3233/JAD-160160

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 209-219, 2016

Authors: Tang, Wei | Cheng, Juan | Wang, Zheng-Yu | Chen, Ke-Yang | Han, Zhen-Min | Wang, Qi-Hong | Yao, Yu-You

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related …mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene. Show more

Keywords: Alzheimer’s disease, amyloid-β, chronic offspring stress, chronic prenatal stress, glucocorticoid, learning and memory impairments

DOI: 10.3233/JAD-160011

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 221-236, 2016

Authors: Amen, Daniel G. | Willeumier, Kristen | Omalu, Bennet | Newberg, Andrew | Raghavendra, Cauligi | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: National Football League (NFL) players are exposed to multiple head collisions during their careers. Increasing awareness of the adverse long-term effects of repetitive head trauma has raised substantial concern among players, medical professionals, and the general public. Objective: To determine whether low perfusion in specific brain regions on neuroimaging can accurately separate professional football players from healthy controls. Method: A cohort of retired and current NFL players (n  = 161) were recruited in a longitudinal study starting in 2009 with ongoing interval follow up. A healthy control group (n  = 124) was separately recruited for comparison. …Assessments included medical examinations, neuropsychological tests, and perfusion neuroimaging with single photon emission computed tomography (SPECT). Perfusion estimates of each scan were quantified using a standard atlas. We hypothesized that hypoperfusion particularly in the orbital frontal, anterior cingulate, anterior temporal, hippocampal, amygdala, insular, caudate, superior/mid occipital, and cerebellar sub-regions alone would reliably separate controls from NFL players. Cerebral perfusion differences were calculated using a one-way ANOVA and diagnostic separation was determined with discriminant and automatic linear regression predictive models. Results: NFL players showed lower cerebral perfusion on average (p  < 0.01) in 36 brain regions. The discriminant analysis subsequently distinguished NFL players from controls with 90% sensitivity, 86% specificity, and 94% accuracy (95% CI 95-99). Automatic linear modeling achieved similar results. Inclusion of age and clinical co-morbidities did not improve diagnostic classification. Conclusion: Specific brain regions commonly damaged in traumatic brain injury show abnormally low perfusion on SPECT in professional NFL players. These same regions alone can distinguish this group from healthy subjects with high diagnostic accuracy. This study carries implications for the neurological safety of NFL players. Show more

Keywords: Brain imaging, cognition, concussion, football, NFL, SPECT, traumatic brain injury

DOI: 10.3233/JAD-160207

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 237-241, 2016

Authors: Maliszewska-Cyna, Ewelina | Xhima, Kristiana | Aubert, Isabelle

Article Type: Research Article

Abstract: Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer’s disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. …After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid pathology, neurogenesis, physical exercise, spatial memory

DOI: 10.3233/JAD-150660

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 243-257, 2016

Authors: Verma, Nirmal | Ly, Han | Liu, Miao | Chen, Jing | Zhu, Haining | Chow, Martin | Hersh, Louis B. | Despa, Florin

Article Type: Research Article

Abstract: Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer’s disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. …Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD. Show more

Keywords: Alzheimer’s disease, amylin, 4-hydroxynonenal, malondialdehyde, neuroinflammation, type-2 diabetes

DOI: 10.3233/JAD-160047

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 259-272, 2016

Authors: Lovell, Mark A. | Lynn, Bert C. | Fister, Shuling | Bradley-Whitman, Melissa | Murphy, M. Paul | Beckett, Tina L. | Norris, Christopher M.

Article Type: Research Article

Abstract: Because traditional approaches to drug development for Alzheimer’s disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment …leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. Overall, our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer’s disease. Show more

Keywords: Amyloid-β protein precursor, Elk-1, presenilin-1, presenilin-2

DOI: 10.3233/JAD-151160

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 273-287, 2016

Authors: Bobkova, Natalia | Vorobyov, Vasily | Medvinskaya, Natalia | Nesterova, Inna | Tatarnikova, Olga | Nekrasov, Pavel | Samokhin, Alexander | Deev, Alexander | Sengpiel, Frank | Koroev, Dmitry | Volpina, Olga

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n  = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the …loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155–164 and 167–176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients. Show more

Keywords: Acetyltransferase, amyloid-beta, cholinergic mediation, Morris water maze, olfactory bulbectomy, spatial memory

DOI: 10.3233/JAD-160146

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 289-301, 2016

Authors: Luis, Elkin | Ortiz, Alexandra | Eudave, Luis | Ortega-Cubero, Sara | Borroni, Barbara | van der Zee, Julie | Gazzina, Stefano | Caroppo, Paola | Rubino, Elisa | D’Agata, Federico | Le Ber, Isabelle | Santana, Isabel | Cunha, Gil | Almeida, Maria R. | Boutoleau-Bretonnière, Claire | Hannequin, Didier | Wallon, David | Rainero, Innocenzo | Galimberti, Daniela | Van Broeckhoven, Christine | Pastor, Maria A. | Pastor, Pau

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1 ), among other genes. Rare SQSTM1 gene mutations have been associated with Paget’s disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 …pathogenic variants (FTD/SQSTM1 mutation carriers; n  = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD ; n  = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n  = 20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern. Show more

Keywords: Dementia, frontotemporal dementia, SQSTM1 protein, voxel-based morphometry

DOI: 10.3233/JAD-160006

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 303-313, 2016

Authors: Ueda, Yukito | Satoh, Masayuki | Tabei, Ken-ichi | Kida, Hirotaka | Ii, Yuichiro | Asahi, Masaru | Maeda, Masayuki | Sakuma, Hajime | Tomimoto, Hidekazu

Article Type: Research Article

Abstract: Background: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer’s disease. Objective: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function. Methods: The subjects were outpatients who visited the memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function. Results: …Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI– group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI– group in Japanese Raven’s coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures. Conclusion: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function. Show more

Keywords: Bleeding, cerebral amyloid angiopathy, dementia, infarct, magnetic resonance imaging, neuropsychological test

DOI: 10.3233/JAD-151008

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 315-325, 2016

Authors: Paholpak, Pongsatorn | Li-Jung, Liang | Carr, Drew R. | Jimenez, Elvira | Barrows, Robin J. | Sabodash, Valeiry | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces. Objective: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer’s disease (eAD) and healthy controls (HC). Method: Fifty picture stimuli were presented to each participant (bvFTD = 12, eAD = 18, HC = 13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The “facial” stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for …each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups. Results: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p  < 0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p  = 0.006 and 0.019, respectively). Conclusion: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer’s disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces. Show more

Keywords: Alzheimer’s disease, eye movements, frontotemporal dementia, social behavior

DOI: 10.3233/JAD-150864

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 327-335, 2016

Authors: Hascup, Kevin N. | Hascup, Erin R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α 7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6–9 month old male C57BL/6J …mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50×100μm) and minimal damage to the surrounding parenchyma (50–100μm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0μM; ∼150 nl; 1-2 Seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0μM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0μM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0μM α -Bungarotoxin, the potent α 7nAChR antagonist. Coapplication of 10.0μM tetrodotoxin, indicates Aβ42 -  induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α 7nAChR and varies across hippocampal subfields. Show more

Keywords: Alpha bungarotoxin, Alzheimer’s disease, amyloid-beta, biosensor, cognition, hippocampus, neurotransmission, nicotinic acetylcholine receptor, presynaptic, tetrodotoxin

DOI: 10.3233/JAD-160041

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 337-347, 2016

Authors: Tajeddinn, Walid | Persson, Torbjörn | Calvo-Garrido, Javier | Seed Ahmed, Mohammed | Maioli, Silvia | Vijayaraghavan, Swetha | Kazokoglu, Mehmet Selim | Parrado-Fernández, Cristina | Yoshitake, Takashi | Kehr, Jan | Francis, Paul | Winblad, Bengt | Höglund, Kina | Cedazo-Minguez, Angel | Aarsland, Dag

Article Type: Research Article

Abstract: Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer’s disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), …SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p  < 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p  > 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression. Show more

Keywords: 5-HT1B receptor, Alzheimer’s disease, APPswe, MAOA, p11, serotonin, SERT

DOI: 10.3233/JAD-160046

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 349-361, 2016

Article Type: Other

DOI: 10.3233/JAD-160381

Citation: Journal of Alzheimer's Disease, vol. 53, no. 1, pp. 363-366, 2016