Pages 271-276
Short Communication
Nathalie Pierrot, Renaud Lhommel, Lisa Quenon, Bernard Hanseeuw, Laurence Dricot, Christian Sindic, Jean-Marie Maloteaux, Jean-Noël Octave, Adrian Ivanoiu
Targretin Improves Cognitive and Biological Markers in a Patient with Alzheimer’s Disease
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.
Pages 277-285
Nagaendran Kandiah*, Vivian Wang*, Xuling Lin, Mei Mei Nyu, Linda Lim, Adeline Ng, Shahul Hameed, Hwee Lin Wee *These authors contributed equally to this work.
Cost Related to Dementia in the Young and the Impact of Etiological Subtype on Cost
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.
Pages 287-300
Tuan Minh Do, Agnès Dodacki, Wael Alata, Frédéric Calon, Sophie Nicolic, Jean-Michel Scherrmann, Robert Farinotti, Fanchon Bourasset (Handling Associate Editor: Othman Ghribi)
Age-Dependent Regulation of the Blood-Brain Barrier Influx/Efflux Equilibrium of Amyloid-β Peptide in a Mouse Model of Alzheimer’s Disease (3xTg-AD)
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 [3H]cholesterol and [3H]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 upregulated 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 upregulation 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.
Pages 301-316
Kelsey R. LeVault, Shelley A. Tischkau, Gregory J. Brewer (Handling Associate Editor: J. Wesson Ashford)
Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model
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.
Pages 317-327
Dipti Jigar Shah, Frederick Rohlfing, Swati Anand, W. Evan Johnson, MeiHwa Tanielle Bench Alvarez, Jesse Cobell, Jackson King, Sydney A. Young, John S.K. Kauwe, Steven W. Graves (Handling Associate Editor: Ram Bishnoi)
Discovery and Subsequent Confirmation of Novel Serum Biomarkers Diagnosing Alzheimer’s Disease
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.
Pages 329-342
Jean-Philippe Coutu, Alison Goldblatt, H. Diana Rosas, David H. Salat and the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Brian Gold)
White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer’s Disease
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.
Pages 343-352
Pau Pastor, Fermín Moreno, Jordi Clarimón, Agustín Ruiz, Onofre Combarros, Miguel Calero, Adolfo López de Munain, Maria J Bullido, Marian M. de Pancorbo, Eva Carro, Anna Antonell, Eliecer Coto, Sara Ortega-Cubero, Isabel Hernandez, Lluís Tárraga, Mercè Boada, Alberto Lleó, Oriol Dols-Icardo, Jaime Kulisevsky, José Luis Vázquez-Higuera, Jon Infante, Alberto Rábano, Miguel Ángel Fernández-Blázquez, Meritxell Valentí, Begoña Indakoetxea, Myriam Barandiarán, Ana Gorostidi , Ana Frank-García, Isabel Sastre, Elena Lorenzo, María A Pastor, Xabier Elcoroaristizabal, Martina Lennarz, Wolfang Maier, Alfredo Rámirez, Manuel Serrano-Ríos, Suzee E Lee, Pascual Sánchez-Juan, on behalf of The Dementia Genetic Spanish Consortium (DEGESCO)
MAPT H1 Haplotype is Associated with Late-Onset Alzheimer’s Disease Risk in APOE ε4 Noncarriers: Results from the Dementia Genetics Spanish Consortium
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 ε4 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=8.59x10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE ε4 AD.
Pages 353-363
Min Xie*, Yun Han*, Quntao Yu, Xia Wang, Shaohui Wang, Xiaomei Liao (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein
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 show 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.
Pages 365-375
Dandan Chu*, Jianxin Tan*, Shutao Xie, Nana Jin, Xiaomin Yin, Cheng-Xin Gong, Khalid Iqbal, Fei Liu (Handling Associate Editor: Jianzhi Wang) *These authors contributed equally to this work.
GSK-3β is Dephosphorylated by PP2A in a Leu309 Methylation-Independent Manner
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.
Pages 377-386
Yongjoon Yoo, Seong A Shin, Soowon Park, Ji-Hye Lee, Jung-Hae Youn, Yu Kyeong Kim, Jun-Young Lee (Handling Associate Editor: Cristian Leyton)
The Korean Size/Weight Attribute Test: A Semantic Knowledge Test for the Korean Older Adults and Brain-Imaging Evidence
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.
Pages 387-398
David Bensamoun, Renaud Guignard, Ansgar J. Furst, Alexandre Derreumaux, Valeria Manera, Jacques Darcourt, Michel Benoit, Philippe Robert, Renaud David, for the Alzheimer’s Disease Neuroimaging Initiative
Associations Between Neuropsychiatric Symptoms and Cerebral Amyloid Deposition in Cognitively Impaired Elderly People
Abstract: Background: Neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect the majority of patients with dementia, and result in a greater cognitive and functional impairment. Objective: To investigate associations between BPSD and amyloid cerebral deposition as measured by 18F-Florbetapir-PET quantitative uptake in elderly subjects with and without cognitive impairment. Methods: Participants with cognitive impairment [mild cognitive impairment (MCI) or Alzheimer’s disease (AD)] and healthy controls (HC) from the ADNI cohort (Alzheimer Disease Neuroimaging Initiative) who underwent an 18F-florbetapir PET scan between May 2010 and March 2014 were included. Clinical assessments included the Clinical Dementia Rating, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Freesurfer software was used to extract PET counts based on T1-based structural ROI (frontal, cingulate, parietal, and temporal). Spearman’s partial correlation scores between BPSD severity and regional amyloid uptake were calculated. Results: Data for 657 participants [age=72.6 (7.19); MMSE=27.4 (2.67)] were analyzed, including 230 HC [age=73.1 (6.02); MMSE=29 (1.21)], 308 MCI [age=71.5 (7.44); MMSE=28.0 (1.75)], and 119 AD subjects [age=74.7 (8.05); MMSE=23.1 (2.08)]. Considering all diagnostic groups together, positive significant correlations were found between anxiety and 18F-florbetapir uptake in the frontal (r=0.102; p=0.009), cingulate (r=0.083; p=0.034), and global cerebral uptake (r=0.099; p=0.011); between irritability and frontal (r=0.089; p=0.023), cingulate (r=0.085; p=0.030), parietal (r=0.087; p=0.025), and global cerebral uptake (r=0.093; p=0.017); in the MCI subgroup, between anxiety and frontal (r=0.126; p=0.03) and global uptake (r=0.14; p=0.013); in the AD subgroup, between irritability and parietal uptake(r=0.201; p=0.03). Conclusion: Anxiety and irritability are associated with greater amyloid deposition in the neurodegenerative process leading to AD.
Pages 399-405
Zhongyong Shi, Yingbo Zhu, Meijuan Wang, Yujie Wu, Jing Cao, Chunbo Li, Zhongcong Xie, Yuan Shen (Handling Associate Editor: Xuemin Xu)
The Utilization of Retinal Nerve Fiber Layer Thickness to Predict Cognitive Deterioration
Abstract: Our previous studies have shown that longitudinal reduction in retinal nerve fiber layer (RNFL) thickness is associated with cognitive deterioration. However, whether the combination of longitudinal reduction in RNFL thickness with baseline episodic memory performance can better predict cognitive deterioration remains unknown. Therefore, we set out to re-analyze the data obtained from our previous studies with 78 elderly adults (mean age 74.4±3.83 years, 48.7% male) in the community over a 25-month period. The participants were categorized as either stable participants whose cognitive status did not change (n=60) or converted participants whose cognitive status deteriorated (n=18). A logistic regression analysis was applied to determine a conversion score for predicting the cognitive deterioration in the participants. We found that the area under the receiver operating characteristic curve (AUC) for the multivariable model was 0.854 (95% CI 0.762-0.947) using baseline story recall as a predictor, but the AUC increased to 0.915 (95% CI 0.849-0.981) with the addition of the longitudinal reduction of RNFL thickness in the inferior quadrant. The conversion score was significantly higher for the converted participants than the stable participants (0.59±0.30 versus 0.12±0.19, p < 0.001). Finally, the optimal cutoff value of the conversion score (0.134) was determined by the analysis of receiver operating characteristic curve, and this conversion score generated a sensitivity of 0.944 and a specificity of 0.767 in predicting the cognitive deterioration. These findings have established a system to perform a larger scale study to further test whether the longitudinal reduction in RNFL thickness could serve as a biomarker of Alzheimer’s disease.
Pages 407-422
Kathleen C. Fraser, Jed A. Meltzer, Frank Rudzicz (Handling Associate Editor: Peter Garrard)
Linguistic Features Identify Alzheimer's Disease in Narrative Speech
Abstract: Background: Although memory impairment is the main symptom of Alzheimer’s disease (AD), language impairment can be an important marker. Relatively few studies of language in AD quantify the impairments in connected speech using computational techniques. Objective: We aim to demonstrate state-of-the-art accuracy in automatically identifying Alzheimer’s disease from short narrative samples elicited with a picture description task, and to uncover the salient linguistic factors with a statistical factor analysis. Methods: Data are derived from the DementiaBank corpus, from which 167 patients diagnosed with "possible" or "probable" AD provide 240 narrative samples, and 97 controls provide an additional 233. We compute a number of linguistic variables from the transcripts, and acoustic variables from the associated audio files, and use these variables to train two machine learning classifiers to distinguish between participants with AD and healthy controls. To examine the degree of heterogeneity of linguistic impairments in AD, we follow an exploratory factor analysis on these measures of speech and language with an oblique promax rotation, and provide interpretation for the resulting factors. Results: We obtain state-of-the-art classification accuracies of over 92% in distinguishing individuals with AD from those without based on short samples of their language on a picture description task. Four clear factors emerge: semantic impairment, acoustic abnormality, syntactic impairment, and information impairment. Conclusion: Modern machine learning and linguistic analysis will be increasingly useful in assessment and clustering of suspected AD.
Pages 423-432
Hemalkumar B. Mehta, Vinay Mehta, Chu-Lin Tsai, Hua Chen, Rajender Aparasu, Michael L. Johnson
Development and Validation of the RxDx-Dementia Risk Index to Predict Dementia in Patients with Type 2 Diabetes and Hypertension
Abstract: Background: Elderly patients with type 2 diabetes mellitus and hypertension are at high risk for developing dementia. In addition to comorbid disease conditions (Dx), prescription drugs (Rx) are important risk factors for dementia. Objective: Develop and validate the RxDx-Dementia risk index by combining diagnosis and prescription information in a single risk index to predict incident dementia, and compare its performance with diagnosis-based Charlson comorbidity score (CCS) and prescription-based chronic disease score (CDS). Methods: Elderly patients diagnosed with type 2 diabetes mellitus and hypertension, and without prior dementia were identified from the Clinical Practice Research Datalink (2003-2012). A Cox proportional hazard model was constructed to model the time to dementia by incorporating age, gender, and 31 RxDx disease conditions as independent variables. Points were assigned to risk factors to obtain summary risk score. Discrimination and calibration of the risk index were evaluated. Different risk indices were compared against RxDx-Dementia risk index using c-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results: Of 133,176 patients with type 2 diabetes mellitus and hypertension, 3.42% patients developed dementia. The c-statistics value for RxDx-Dementia risk index was 0.806 (95% CI, 0.799-0.812). Based on the c-statistics, NRI and IDI values, the RxDx-Dementia risk index performed better compared to CCS, CDS, and their combinations. Conclusion: The RxDx-Dementia risk index can be a useful tool to identify hypertensive and diabetic patients who are at high risk of developing dementia. This has implications for clinical management of patients with multiple comorbid conditions as well as risk adjustment for database studies.
Pages 433-441
Pauline Joussain*, Marion Bessy*, Arnaud Fournel, Camille Ferdenzi, Catherine Rouby, Floriane Delphin-Combe, Pierre Krolak-Salmon, Moustafa Bensafi (Handling Associate Editor: Carlo Abbate) *These authors contributed equally to this work.
Altered Affective Evaluations of Smells in Alzheimer’s Disease
Abstract: Background. Studies of olfaction in Alzheimer’s disease (AD) mainly focused on deficits in odor detection and identification, with very few investigations of olfactory emotional changes and their consequences for hedonics. Objective. The aim of the present study was to characterize affective evaluations of odors in AD patients. Methods. To this end, 20 AD patients and 20 matched controls were tested. Participants were screened for odor detection and identification ability and then asked to rate the intensity, pleasantness, and edibility of 20 odorants. Results. Results showed that, overall, AD patients had lower detection ability and perceived all odors as weaker than controls. As expected, they had lower identification ability on both cued and non-cued tasks. In addition, when smelling pleasant odors, patients had significantly lower hedonic ratings than controls (p<0.02), whereas no group difference was found for neutral or unpleasant odors (p>0.05 in both cases). Moreover, an analysis combining both intensity and pleasantness ratings showed that whereas intensity increased as a function of pleasantness and unpleasantness in controls, this quadratic relationship was not observed in AD patients. Conclusions. The study suggests that the simplest categorization criteria of odors (intensity and hedonic valence) are impaired in AD patients (especially for pleasant odors).
Pages 443-457
Zoltán Rusznák*, Woojin Scott Kim*, Jen-Hsiang T. Hsiao, Glenda M. Halliday, George Paxinos, YuHong Fu (Handling Associate Editor: Ralph Martins) *These authors contributed equally to this work.
Early in vivo Effects of the Human Mutant Amyloid-β Protein Precursor (hAβPPSwInd) on the Mouse Olfactory Bulb
Abstract: The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer’s disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57 ± 0.13 million versus 6.59 ± 0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617 ± 425 versus 4455 ± 623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical.
Pages 459-481
Mario Díaz, Noemí Fabelo, Verónica Casañas-Sánchez, Raquel Marin, Tomás Gómez, David Quinto-Alemany, José A. Pérez
Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer’s Disease
Abstract: Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer’s disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.
Pages 483-491
Byoung Seok Ye, Eun Young Jang, Seong Yoon Kim, Eun-Joo Kim, Sun Ah Park, Yunhwan Lee, Chang Hyung Hong, Seong Hye Choi, Bora Yoon, Soo Jin Yoon, Hae Ri Na, Jae-Hong Lee, Jee H. Jeong, Hee Jin Kim, Duk L. Na, Sang Won Seo
Unstable Body Mass Index and Progression to Probable Alzheimer’s Disease Dementia in Patients with Amnestic Mild Cognitive Impairment
Abstract: Background and Objective: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. Methods: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer’s disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. Results: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controlling for baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. Conclusions: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.
Pages 493-502
Guro Berge, Camilla Lauridsen, Sigrid Botne Sando, Daniel Holder , Ina Møller, Jan Olav Aasly, Geir Bråthen, Mary Savage, Linda Rosemary White
Effect of Tween-20 on Core Biomarkers Measured in Cerebrospinal Fluid from Patients with Alzheimer’s Disease, Mild Cognitive Impairment, or Healthy Control Individuals
Abstract: Background: There is substantial variation caused by preanalytical procedures in the measurement of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) reported in the literature. Objective: Determine whether the detergent Tween-20 improves diagnostic accuracy. Methods: CSF proteins (Aβ42, Aβ40, total tau, and phosphorylated tau) were measured by standard ELISA, in uncentrifuged CSF with or without 0.05% Tween-20 from patients with AD or amnestic mild cognitive impairment, and healthy elderly controls. In the main study collection tubes containing Tween-20 (Sarstedt 15 mL) were filled with 5 mL CSF to ensure consistent detergent concentration across subsequent aliquots into Corning 2 mL tubes. These latter were also the primary collection vessel for samples without Tween-20. The effect of centrifugation, and extra tube transfer of samples with Tween-20 were also examined. Results: 0.05% Tween-20 significantly increased mean measured CSF concentration of Aβ42 (30%), Aβ40 (23%), and total tau (4%), but not phosphorylated tau. Generally, these increases were similar in all groups, although for Aβ42, the mean percentage increase with Tween-20 was slightly larger for AD. Areas under receiver-operator characteristic curves were similar whether Tween-20 was present or not. Centrifuged CSF without Tween-20 significantly reduced the measured concentration of Aβ42 versus non-centrifuged samples, a difference not seen when detergent was added. Similar CSF Aβ42 levels were found whether Tween-20 was added at collection in an extra tube or directly to the main collection tube. Conclusion: Addition of Tween-20 to CSF did not improve differentiation of patients from controls.
Pages 503-513
Kaori Miwa, Makiko Tanaka, Shuhei Okazaki, Yoshiki Yagita, Manabu Sakaguchi, Hideki Mochizuki, Kazuo Kitagawa
Increased Total Homocysteine Levels Predict the Risk of Incident Dementia Independent of Cerebral Small-Vessel Diseases and Vascular Risk Factors
Abstract: Background: Homocysteine has been identified as a potential risk factor for stroke, cerebral small-vessel diseases (SVD), and dementia. Objective: The present study aimed to investigate the predictive value of homocysteine levels on incident dementia while simultaneously controlling for MRI findings and vascular risk factors. Methods: Within a Japanese cohort of participants with vascular risk factors in an observational study, we evaluated the association between baseline total homocysteine (tHcy) levels (per 1 μmol/L and the tertile of tHcy), the prevalence of MRI-findings at baseline, and incident all-cause dementia. Baseline brain MRI was used to determine SVD (lacunas, white matter hyperintensities, and cerebral microbleeds [CMBs]) and atrophy (medial-temporal lobe atrophy and bicaudate ratio). Logistic regression analyses were used to estimate the cross-sectional association between tHcy and each of MRI findings. Cox proportional hazards analyses were performed to estimate the longitudinal association between tHcy and dementia. Results: In the 643 subjects (age: 67.2±8.4 years, male: 59%; education: 12.9±2.6 years), multivariable analyses adjusted for several potential confounders, including estimated glomerular filtration rate (eGFR) and intima-media thickness, showed that highest tHcy tertile was associated with lacunas, CMBs, and strictly deep CMBs. During the mean 7.3-year follow-up (range: 2-13), 47 patients were diagnosed with dementia (Alzheimer’s disease: 24; vascular dementia: 18; mixed-type: 3; other: 2). After adjusting for age, gender, APOE ε4, education, BMI, MMSE, hypertension, cerebrovascular events, eGFR, and MRI-findings, tHcy level (hazard ratios [HR]: 1.08, p=0.043) and the highest tertile of tHcy (HR: 2.50, p=0.047) for all-cause dementia remained significant. Conclusions: Our results provide additional evidence of tHcy that contributes to increased susceptibility to dementia risk.
Mini-Forum on The Assessment of Dementia by the Latent Variable 'δ' (Guest Editor: Donald Royall)
Pages 515-519
Editorial
Donald R. Royall
Welcome Back to Your Future: The Assessment of Dementia by the Latent Variable “δ”
Pages 521-529
Raymond F. Palmer, Donald R. Royall
Future Dementia Severity is Almost Entirely Explained by the Latent Variable δ’s Intercept and Slope
Abstract: Background: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct “δ” (for dementia) provides a relatively "error free" continuously varying dementia-specific phenotype. Objective: To estimate δ’s change over time (Δδ) and determine Δδ’s predictive validity using future dementia status as an outcome. Methods: Data from n = 2,191 participants of the Texas Alzheimer’s Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily Living. Four final latent factors, including baseline δ and Δδ, were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale “sum of boxes” (CDR). Results: All observed measures exhibited significant change [χ2 = 1,152 (df =229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ2 = 543 (df =245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g’ significantly explained 3% of CDR4 variance independently of d and Δd. Δg’ was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance. Conclusions: Future dementia severity is almost entirely explained by the latent construct δ’s intercept and slope.
Pages 531-545
Brandon E. Gavett, Samantha E. John, Ashita S. Gurnani, Cara A. Bussell, Jessica L. Saurman
The Role of Alzheimer’s and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer’s Disease
Abstract: Background. Dementia severity can be modeled as the construct δ, representing the “cognitive correlates of functional status.” Objective. We recently validated a model for estimating δ in the National Alzheimer’s Coordinating Center’s Uniform Data Set; however, the association of δ with neuropathology remains untested. Methods. We used data from 727 decedents evaluated at Alzheimer’s Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants’ last visit prior to death were used to estimate dementia severity (δ). Results. A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ε2 and ε4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ε2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ε4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD. Conclusions. Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.
Pages 547-560
Alexander Koppara*, Steffen Wolfsgruber*, Luca Kleineidam*, Klaus Schmidtke, Lutz Frölich, Alexander Kurz, Stefanie Schulz, Harald Hampel, Isabella Heuser, Oliver Peters, Friedel M. Reischies, Holger Jahn, Christian Luckhaus, Michael Hüll , Hermann-Josef Gertz, Johannes Schröder, Johannes Pantel, Otto Rienhoff, Eckart Rüther, Fritz Henn, Jens Wiltfang, Wolfgang Maier, Frank Jessen, Johannes Kornhuber, Michael Wagner *These authors contributed equally to this work.
The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment
Abstract: Background: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer’s disease (AD) research and clinical trials. Objective: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. Results: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p<0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC =0.84, p<0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. Conclusion: These findings support the interpretation of δ as a construct capturing the disease-related “essence” of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.
Pages 561-570
Donald R. Royall, Raymond F. Palmer, Teruyuki Matsuoka, Yuka Kato, Shogo Taniguchi, Mayu Ogawa, Hiroshi Fujimoto, Aiko Okamura, Keisuke Shibata, Kaeko Nakamura, Shutaro Nakaaki, Hiroyuki Koumi, Masaru Mimura, Kenji Fukui, Jin Narumoto
δ Scores are Exportable Across Cultural and Linguistic Boundaries
Abstract: The latent variable “δ”, can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog (“dT2J”) in data collected by the Texas Alzheimer’s Research and Care Consortium (TARCC). From this, we calculated a composite d-score “d”. We then tested d’s generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, “T2J”, was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d score composites can be abstracted from a subset of δ’s indicators. Moreover, those composites are exportable across cultural and linguistic boundaries.
Pages 571-579
Donald R. Royall, Raymond F. Palmer, Teruyuki Matsuoka, Yuka Kato, Shogo Taniguchi, Mayu Ogawa, Hiroshi Fujimoto, Aiko Okamura, Keisuke Shibata, Kaeko Nakamura, Shutaro Nakaaki, Hiroyuki Koumi, Masaru Mimura, Kenji Fukui, Jin Narumoto
Greater than the Sum of Its Parts: δ can be Constructed from Item Level Data
Abstract: “δ”, a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, “dTEXAS”, from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r = -0.86, p <0.001) and Clinical Dementia Rating Scale (CDR) (r = 0.71, p <0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls (area under the receiver operating curve [(AUC; ROC) = 0.92], dementia versus mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74). These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of -0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity.
Page 581
Book Review: Recent Advances in Alzheimer Research (Volume 1): Common Pathogenic Mechanisms between Down Syndrome and Alzheimer's Disease: Steps toward Therapy, Edited by Ahmad Salehi, Michael Rafii, and Cristy Phillips, Published by Bentham Science Publishers. September 2015. eISBN: 9781681081380. Reviewed by J. Wesson Ashford
