Journal of Alzheimer's Disease - Volume 49, issue 2

Authors: Pierrot, Nathalie | Lhommel, Renaud | Quenon, Lisa | Hanseeuw, Bernard | Dricot, Laurence | Sindic, Christian | Maloteaux, Jean-Marie | Octavea, Jean-Noël | Ivanoiu, Adrian

Article Type: Short Communication

Abstract: We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer’s disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage …of AD. Show more

Keywords: Amyloid-β and tau markers, cholesterol, cognition, Targretin/bexarotene

DOI: 10.3233/JAD-150405

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 271-276, 2016

Authors: Kandiah, Nagaendran | Wang, Vivian | Lin, Xuling | Nyu, Mei Mei | Lim, Linda | Ng, Adeline | Hameed, Shahul | Wee, Hwee Lin

Article Type: Research Article

Abstract: Background: Young onset dementia (YOD) presents in individuals who are economically productive and socially active. While the cost related to dementia in the elderly has been widely studied, the cost related to YOD is largely unknown. Objective: To study the economic burden of community dwelling YOD in relation to late onset dementia (LOD) and cost of YOD based on etiology. Methods: In this prospective cross-sectional study of 255 patients attending a tertiary neurology center, data on economic burden, clinical features, and caregiver burden were collected using structured financial questionnaire, standard cognitive and neuropsychiatric measures, and Zarit …caregiver burden scale. Cost components were grouped into those relating to direct medical costs, direct non-medical costs, and those related to indirect costs. Cost was also categorized based on etiology of YOD. Results: The mean age at symptom onset in the YOD and LOD cohort was 57.0 (SD 5.1) and 75.0 (SD 5.9) years, respectively. The median annual cost for patients with YOD was almost twice that of LOD (USD 15,815 versus USD 8,396). Indirect cost contributed heavily to cost related to YOD. Even when grouped by dementia etiology, YOD patients with Alzheimer’s disease, frontotemporal dementia (FTD), and vascular dementia had higher cost compared to their elderly counterparts. Young onset FTD had the highest cost. 43.2% of YOD reported loss of employment due to dementia, which was significantly higher than that in LOD (2.4%). Conclusion: Patients with YOD have a high economic burden. Young patients with FTD have the highest cost followed by vascular dementia and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, economic burden, frontotemporal dementia, young-onset dementia

DOI: 10.3233/JAD-150471

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 277-285, 2016

Authors: Do, Tuan Minh | Dodacki, Agnès | Alata, Wael | Calon, Frederic | Nicolic, Sophie | Scherrmann, Jean-Michel | Farinotti, Robert | Bourasset, Fanchon

Article Type: Research Article

Abstract: The involvement of transporters located at the blood-brain barrier (BBB) has been suggested in the control of cerebral Aβ levels, and thereby in Alzheimer’s disease (AD). However, little is known about the regulation of these transporters at the BBB in animal models of AD. In this study, we investigated the BBB expression of Aβ influx (Rage) and efflux (Abcb1-Abcg2-Abcg4-Lrp-1) transporters and cholesterol transporter (Abca1) in 3–18-month-old 3xTg-AD and control mice. The age-dependent effect of BBB transporters regulation on the brain uptake clearance (Clup ) of [3 H]cholesterol and [3 H]Aβ1 - 40 was then evaluated in these mice, using the in …situ brain perfusion technique. Our data suggest that transgenes expression led to the BBB increase in Aβ influx receptor (Rage) and decrease in efflux receptor (Lrp-1). Our data also indicate that mice have mechanisms counteracting this increased net influx. Indeed, Abcg4 and Abca1 are up regulated in 3- and 3/6-month-old 3xTg-AD mice, respectively. Our data show that the balance between the BBB influx and efflux of Aβ is maintained in 3 and 6-month-old 3xTg-AD mice, suggesting that Abcg4 and Abca1 control the efflux of Aβ through the BBB by a direct (Abcg4) or indirect (Abca1) mechanism. At 18 months, the BBB Aβ efflux is significantly increased in 3xTg-AD mice compared to controls. This could result from the significant up-regulation of both Abcg2 and Abcb1 in 3xTg-AD mice compared to control mice. Thus, age-dependent regulation of several Aβ and cholesterol transporters at the BBB could ultimately limit the brain accumulation of Aβ. Show more

Keywords: ABCA1, ABCB1, ABCG2, ABCG4, Alzheimer’s disease, amyloid-β, blood-brain barrier, cholesterol, Oatp1a4, RAGE, 3xTg-AD

DOI: 10.3233/JAD-150350

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 287-300, 2016

Authors: LeVault, Kelsey R. | Tischkau, Shelley A. | Brewer, Gregory J.

Article Type: Research Article

Abstract: It is unclear whether pre-symptomatic Alzheimer’s disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2–/– model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both …genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels. Show more

Keywords: Alzheimer’s disease, APPSwDI NOS2–/–, circadian disruption, glutathione, GSH, jet lag, learning, memory, redox, sleep

DOI: 10.3233/JAD-150026

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 301-316, 2016

Authors: Shah, Dipti Jigar | Rohlfing, Frederick | Anand, Swati | Johnson, W. Evan | Alvarez, MeiHwa Tanielle Bench | Cobell, Jesse | King, Jackson | Young, Sydney A. | Kauwe, John S.K. | Graves, Steven W.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) remains challenging to diagnose, especially early disease. Having serum AD biomarkers would be of significant interest both in the clinical setting and in drug development efforts. Objective: We applied a novel serum proteomic approach to interrogate the low-molecular weight proteome for serum AD biomarkers. Methods: A discovery study used sera from 58 any-stage AD cases and 55 matched controls analyzed by capillary liquid chromatography-electrospray ionization-tandem mass spectrometry. Candidate biomarkers were statistically modeled and promising biomarkers were retested in a second, blinded confirmatory study (AD cases = 68, controls = 57). Biomarkers that replicated in the second …study were modeled for the diagnosis of any-stage and very early stage AD. Further, they were chemically identified by tandem MS. Results: The initial discovery study found 59 novel potential AD biomarkers. Thirteen recurred in more than one multi-marker panel. In a second, blinded, confirmatory study, these same biomarkers were retested in separate specimens. In that study, four markers validated comparing controls to patients with any-stage AD and also with very early AD. The four biomarkers with replicable ability to diagnose AD were then chemically identified. Conclusion: These results suggest novel serum AD diagnostic biomarkers can be found using this approach. Show more

Keywords: Alzheimer’s disease, diagnosis, lipidomics, mass spectrometry, proteomics, serum biomarkers

DOI: 10.3233/JAD-150498

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 317-327, 2016

Authors: Coutu, Jean-Philippe | Goldblatt, Alison | Rosas, H. Diana | Salat, David H.

Article Type: Research Article

Abstract: White matter lesions are highly prevalent in individuals with Alzheimer’s disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1 -weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older …adults and individuals with mild cognitive impairment and AD using data from the Alzheimer’s Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, cerebral ventricles, diffusion tensor imaging, hippocampus, leukoaraiosis, mild cognitive impairment, white matter

DOI: 10.3233/JAD-150306

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 329-342, 2016

Authors: Pastor, Pau | Moreno, Fermín | Clarimón, Jordi | Ruiz, Agustín | Combarros, Onofre | Calero, Miguel | de Munain, Adolfo López | Bullido, Maria J. | de Pancorbo, Marian M. | Carro, Eva | Antonell, Anna | Coto, Eliecer | Ortega-Cubero, Sara | Hernandez, Isabel | Tárraga, Lluís | Boada, Mercè | Lleó, Alberto | Dols-Icardo, Oriol | Kulisevsky, Jaime | Vázquez-Higuera, José Luis | Infante, Jon | Rábano, Alberto | Fernández-Blázquez, Miguel Ángel | Valentí, Meritxell | Indakoetxea, Begoña | Barandiarán, Myriam | Gorostidi, Ana | Frank-García, Ana | Sastre, Isabel | Lorenzo, Elena | Pastor, María A. | Elcoroaristizabal, Xabier | Lennarz, Martina | Maier, Wolfang | Rámirez, Alfredo | Serrano-Ríos, Manuel | Lee, Suzee E. | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer’s disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson’s disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR) = 2.03; p  = 0.063], but not with AD. MAPT H1 haplotype was associated …with AD risk (OR = 1.12; p  = 0.0005). Stratification analysis showed that this association was mainly driven by APOE ɛ 4 noncarriers (OR = 1.14; p  = 0.0025). MAPT H1 was also associated with risk for PD (OR = 1.30; p  = 0.0003) and PSP (OR = 3.18; p  = 8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ɛ 4 AD. Show more

Keywords: A152T, Alzheimer’s disease, frontotemporal dementia, genetic association, H1H2, MAPT

DOI: 10.3233/JAD-150555

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 343-352, 2016

Authors: Xie, Min | Han, Yun | Yu, Quntao | Wang, Xia | Wang, Shaohui | Liao, Xiaomei

Article Type: Research Article

Abstract: Ubiquitin C-terminal hydrolase L1 (UCH-L1) is critical for protein degradation and free ubiquitin recycling. In Alzheimer’s disease brains, UCH-L1 is negatively related to neurofibrillary tangles whose major component is hyperphosphorylated tau protein, but the direct action of UCH-L1 on tau has not been reported. In the current study, mouse neuroblastoma Neuro2a (N2a) cells were treated by the different concentrations of UCH-L1 inhibitor LDN (2.5, 5 and 10 μM) to inhibit the hydrolase activity of UCH-L1. In addition, we also used UCH-L1 siRNA to treat the HEK293/tau441 cells to decrease the expression of UCH-L1. After LDN and UCH-L1 siRNA treatment, we …used immunofluorescence, immunoprecipitation, and tau-microtubule binding assay to measure the microtubule-binding ability and post-translational modifications of tau protein. All the results presented that both inhibition of the activity and expression of UCH-L1 induced the decreased microtubule-binding ability and increased phosphorylation of tau protein. Abnormal aggregation and ubiquitination of tau protein was also observed after UCH-L1 inhibition. The above results suggested that aggregation of tau protein might be devoted to the abnormal post-translational modifications of tau protein. Our study first indicates that dysfunction of UCH-L1 most likely affected normal biological function of tau protein through decreasing degradation of ubiquitinated and hyperphosphorylated tau. Show more

Keywords: Aggregation, microtubule-binding function, post-translational modification, tau protein, UCH-L1 inhibition

DOI: 10.3233/JAD-150032

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 353-363, 2016

Authors: Chu, Dandan | Tan, Jianxin | Xie, Shutao | Jin, Nana | Yin, Xiaomin | Gong, Cheng-Xin | Iqbal, Khalid | Liu, Fei

Article Type: Research Article

Abstract: Hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer’s disease (AD) and related tauopathies. Glycogen synthase kinase-3β (GSK-3β) and protein phosphate 2A (PP2A) are crucial enzymes to regulate tau phosphorylation. GSK-3β activity is regulated by its inhibitory phosphorylation at Ser9. We previously reported the cross-talk between GSK-3β and PP2A signaling and showed that PP2A could dephosphorylate GSK-3β at Ser9. Here, we investigated the dephosphorylation of GSK-3β in brain extracts in the presence of phosphatase inhibitors and found that a PP2A-like phosphatase activity was required for dephosphorylation of GSK-3β at Ser9. PP2A interacted with GSK-3β and suppressed its Ser9 …phosphorylation in vitro and in HEK-293FT cells. Activity of PP2A negatively correlated to the level of phosphorylated GSK-3β in kainic acid-induced excitotoxic mouse brain. Alteration of methylation of the catalytic subunit of PP2A (PP2Ac) at Leu309 did not affect GSK-3β phosphorylation. These findings suggest that Leu309 methylation is not required for PP2A to dephosphorylate GSK-3β at Ser9. Show more

Keywords: GSK-3β, methylation, phosphorylation, PP2A

DOI: 10.3233/JAD-150497

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 365-375, 2016

Authors: Yoo, Yongjoon | Shin, Seong A. | Park, Soowon | Lee, Ji-Hye | Youn, Jung-Hae | Kim, Yu Kyeong | Lee, Jun-Young

Article Type: Research Article

Abstract: Background: A standardized tool for evaluating semantic knowledge of the Korean population is needed. Objective: The purpose of this study was to develop a neuropsychological test for the evaluation of semantic knowledge in the Korean elderly population. Methods: The Korean version of the Size/Weight Attribute Test (SWAT-K) was developed in reference to the original version. The diagnostic validity of SWAT-K was evaluated with 95 elderly outpatients [67 normal controls; 18 with Alzheimer’s disease (AD); 10 with semantic-variant progressive aphasia (SV-PPA)]. Voxel-based morphometry (VBM) was employed to examine associations between SWAT-K scores and morphological changes of the …brain. Results: SWAT-K could discriminate the three subject groups (normal >AD, p  <  0.001; AD >SV-PPA, p  = 0.040), whereas Boston Naming Test could not distinguish SV-PPA from AD. ROC curve analysis confirmed high levels of sensitivity (0.90) and specificity (0.93) for SWAT-K. The test’s inter-rater reliability (ICC = 0.827) and test-retest reliability (ICC = 0.666) were assessed as well. VBM found a significant positive correlation (uncorrected p  <  0.005, k  >  100) between SWAT-K scores and gray matter volume in right inferior frontal cortex (T  = 4.08, k  = 191) and bilateral temporal cortices (left, T  = 4.42, k  = 135; right, T  = 3.55, k  = 253), the areas the most affected in SV-PPA. Conclusions: SWAT-K is a sensitive and reliable test for evaluating semantic knowledge in the Korean elderly population. Strong positive correlations between SWAT-K scores and the brain areas responsible for semantic processing further corroborate the validity of SWAT-K. Show more

Keywords: Aged, aphasia, primary progressive, cognition, frontotemporal dementia, imaging, three-dimensional, language, neuropsychological tests, semantics

DOI: 10.3233/JAD-150492

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 377-386, 2016