Journal of Alzheimer's Disease - Volume 28, issue 3

Authors: Chace, Constance | Pang, Deborah | Weng, Catherine | Temkin, Alexis | Lax, Simon | Silverman, Wayne | Zigman, Warren | Ferin, Michel | Lee, Joseph H. | Tycko, Benjamin | Schupf, Nicole

Article Type: Research Article

Abstract: CYP17 and CYP19 are involved in the peripheral synthesis of estrogens, and polymorphisms in CYP17 and CYP19 have been associated with increased risk of estrogen-related disorders. Women with Down syndrome (DS) have early onset and high risk for Alzheimer's disease (AD). We conducted a prospective community-based cohort study to examine the relationship between SNPs in CYP17 and CYP19 and cumulative incidence of AD, hormone levels and sex hormone binding globulin in women with DS. Two hundred and thirty-five women with DS, 31 to 67 years of age and nondemented at initial examination, were assessed for cognitive and functional abilities, behavioral/psychiatric …conditions, and health status at 14–20 month intervals over five assessment cycles. We genotyped these individuals for single-nucleotide polymorphisms (SNPs) in CYP17 and CYP19. Four SNPs in CYP17 were associated with a two and one half-fold increased risk of AD, independent of APOE genotype. Four SNPs in CYP19 were associated with a two-fold increased risk of AD, although three were significant only in those without an APOE ε4 allele. Further, carrying high risk alleles in both CYP17 and CYP19 was associated with an almost four-fold increased risk of AD (OR = 3.8, 95% CI, 1.6–9.5) and elevated sex hormone binding globulin in postmenopausal women. The main effect of the CYP17 and CYP19 variants was to decrease the age at onset. These findings suggest that genes contributing to estrogen bioavailability influence risk of AD in women with DS. Show more

Keywords: Alzheimer's disease, aromatase, CYP17, CYP19, Down syndrome, estrogen, genetics

DOI: 10.3233/JAD-2011-110860

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 601-612, 2012

Authors: Kamer, Angela R. | Morse, Douglas E. | Holm-Pedersen, Poul | Mortensen, Erik L. | Avlund, Kirsten

Article Type: Research Article

Abstract: Inflammation plays a significant role in Alzheimer's disease (AD) pathogenesis. Studies have shown that systemic, peripheral infections affect AD patients. Cognitive dysfunction is a consistent finding in AD and periodontal disease is a chronic, peripheral infection often resulting in tooth loss. We hypothesized that older adults with periodontal inflammation (PI) or many missing teeth would show impaired cognition compared to subjects without PI or with few missing teeth, and among subjects with PI, those with many missing teeth would show impaired cognition compared to those with few missing teeth. The effect of PI/tooth loss on cognitive function [measured by Digit …Symbol (DST) and Block Design (BDT) tests] was assessed in 70-year old Danish subjects. We found: 1) subjects with PI obtained lower mean DST scores compared to subjects without PI (p < 0.05); 2) subjects with many missing teeth had lower mean DST and BDT scores compared to subjects with few missing teeth (p < 0.05); 3) the association of PI with DST and BDT scores was dependant on the number of missing teeth (interaction: p = 0.03 and p = 0.06); and 4) education and previous cognitive scores (age 50) were important covariates. Subjects with PI had significantly lower adjusted mean DST scores compared to subjects without PI. However for adjusted BDT, the significance held only for subjects with few missing teeth. No difference in the adjusted DST and BDT scores was seen between subjects with many missing teeth compared to those with few missing teeth. These results support the hypothesis that PI may affect cognition. Show more

Keywords: Alzheimer's disease, BDT, cognition, DST, inflammation, periodontal disease, tooth loss

DOI: 10.3233/JAD-2011-102004

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 613-624, 2012

Authors: Vafadar-Isfahani, Baharak | Ball, Graham | Coveney, Clare | Lemetre, Christophe | Boocock, David | Minthon, Lennart | Hansson, Oskar | Miles, Amanda Kathleen | Janciauskiene, Sabina M | Warden, Donald | Smith, A. David | Wilcock, Gordon | Kalsheker, Noor | Rees, Robert | Matharoo-Ball, Balwir | Morgan, Kevin

Article Type: Research Article

Abstract: We have used proteomic fingerprinting to investigate diagnosis of Alzheimer's disease (AD). Samples of lumbar cerebrospinal fluid (CSF) from clinically-diagnosed AD cases (n = 33), age-matched controls (n = 20), and mild cognitive impairment (MCI) patients (n = 10) were used to obtain proteomic profiles, followed by bioinformatic analysis that generated a set of potential biomarkers in CSF samples that could discriminate AD cases from controls. The identity of the biomarker ions was determined using mass spectroscopy. The panel of seven peptide biomarker ions was able to discriminate AD patients from controls with a median accuracy of 95% (sensitivity 85%, …specificity 97%). When this model was applied to an independent blind dataset from MCI patients, the intensity of signals was intermediate between the control and AD patients implying that these markers could potentially predict patients with early neurodegenerative disease. The panel were identified, in order of predictive ability, as SPARC-like 1 protein, fibrinogen alpha chain precursor, amyloid-β, apolipoprotein E precursor, serum albumin precursor, keratin type I cytoskeletal 9, and tetranectin. The 7 ion ANN model was further validated using an independent cohort of samples, where the model was able to classify AD cases from controls with median accuracy of 84.5% (sensitivity 93.3%, specificity 75.7%). Validation by immunoassay was performed on the top three identified markers using the discovery samples and an independent sample cohort which was from postmortem confirmed AD patients (n = 17). Show more

Keywords: Alzheimer's disease, biomarker, MALDI-MS, SPARCL1

DOI: 10.3233/JAD-2011-111505

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 625-636, 2012

Authors: Wang, Huifen | Odegaard, Andrew | Thyagarajan, Bharat | Hayes, Jennifer | Cruz, Karen Santa | Derosiers, Mark F. | Tyas, Suzanne L. | Gross, Myron D.

Article Type: Research Article

Abstract: Asymptomatic and partially symptomatic Alzheimer's disease (APSYMAD) are a series of cognitive states wherein subjects have substantial Alzheimer's disease (AD) pathology (classification B or C by the Consortium to Establish a Registry for AD criteria), but have normal or only partially impaired cognitive function; all of these subjects are non-demented. These cognitive states may arise from the prevention or delay of clinical symptom expression by exposure to certain nutritional factors. This study examined blood levels of folate and antioxidants (i.e., carotenoids) in relation to APSYMAD, nested in the Nun study, a longitudinal study of aging and AD. Sixty elderly female …subjects, who had AD on the basis of neuropathology exams, were included. Following adjustment for APOE4 status, education level, and age at blood draw, subjects with the highest blood folate levels had a higher likelihood of being in the APSYMAD group as compared to the demented (AD) group (odds ratio = 1.09, 95% CI = 1.00–1.18. p < 0.06). This association was not significantly influenced by additional adjustment for blood concentrations of carotenoids. Restriction of the population to subjects with near normal cognition on the cognitive state score (score = 1–3) indicated an elevated association with blood folate (odds ratio = 1.12, 95% CI = 1.01–1.25, p < 0.04). Blood carotenoids were not associated with APSYMAD. Thus, folate status may influence the expression of clinical symptoms of AD disease and aid in the delay or prevention of dementia. Show more

Keywords: Alzheimer's disease, asymptomatic, carotenoids, folate

DOI: 10.3233/JAD-2011-111271

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 637-645, 2012

Authors: Soto, Maria E. | Secher, Marion | Gillette-Guyonnet, Sophie | van Kan, Gabor Abellan | Andrieu, Sandrine | Nourhashemi, Fati | Rolland, Yves | Vellas, Bruno

Article Type: Research Article

Abstract: Weight loss is a frequent complication of Alzheimer's disease (AD) and a strong predictor of adverse outcomes in patients suffering from this disease. The aim of this study was to determine whether weight loss was a predictor of rapid cognitive decline (RCD) in AD. Four hundred fourteen community-dwelling ambulatory patients with a diagnosis of probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 26 from the REAL.FR (REseau sur la maladie d'ALzheimer FRançais) cohort were studied and followed up during 4 years. Patients were classified in 2 groups according to weight loss defined by a loss of …4% or more during the first year of follow-up. RCD was defined as the loss of 3 points or more in MMSE over 6 months. The incidence of RCD was determined among both groups over the last 3 years of follow-up. MMSE, Katz's Activity of Daily Living scale, Mini-Nutritional Assessment scale, co-morbidities, behavioral and psychological symptoms of dementia, medication, level of education, living arrangement, and caregiver's burden were assessed every 6 months. Eighty-seven patients (21.0%) lost 4% or more of their initial weight during the first year. The incidence of RCD for all patients was 57.6 (95% confidence interval (CI) = 51.6–64.8) per 100 person-year (median follow-up of 15.1 months). In Cox proportional hazards models, after controlling for potential confounders, weight loss was a significant predictor factor of RCD (adjusted hazard ratio (HR) = 1.50, 95% CI = 1.04–2.17). In conclusion, weight loss predicted RCD in this cohort. Whether the prevention of weight loss (by improving nutritional status) impacts cognitive decline remains an open question. Show more

Keywords: Alzheimer's disease, cognitive decline, weight loss

DOI: 10.3233/JAD-2011-110713

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 647-654, 2012

Authors: Zhang, Cheng | Rodriguez, Cynthia | Spaulding, James | Aw, Tak Yee | Feng, June

Article Type: Research Article

Abstract: Glutathione plays an essential role in the intracellular antioxidant defense against oxidant radicals, especially the •OH radical. To understand the early and progressive cellular changes in the development of Alzheimer's disease (AD), we investigated reduced glutathione/oxidized glutathione (GSH/GSSG) status in a double mutated AD transgenic mouse model (B6.Cg-Tg), which carries Swedish amyloid-β protein precursor mutation (AβPPswe ) and exon 9 deletion of the PSEN1 gene. In this study, we quantified and compared both GSH/GSSG and mixed-disulfide (Pr-SSG) levels in blood samples and three anatomic positions in brain (cerebrum, cerebellum, and hippocampus) at 3 age stages (1, 5, and 11 months) …of AD transgenic (Tg)/wild type mice. The present study was designed to characterize and provide insight into the glutathione redox state of both brain tissues and blood samples at different disease stages of this Tg model. The level of Pr-SSG increased in all AD brain tissues and blood compared with controls regardless of age. The GSH/GSSG ratio in AD-Tg brain tissue started at a higher value at 1 month, fell at the transitional period of 5 months, right before the onset of amyloid plaques, followed by an increase in GSSG and associated decrease of GSH/GSSG at 11 months. These results suggest that formation of Pr-SSG may be an early event, preceding amyloid plaque appearance, and the data further implies that tissue thiol redox is tightly regulated. Notably, the high basal levels of mixed-disulfides in hippocampus suggest a potential for increased oxidative damage under oxidizing conditions and increased GSSG in this vulnerable region. Show more

Keywords: Alzheimer's disease, glutathione, mixed disulfide, oxidized glutathione

DOI: 10.3233/JAD-2011-111244

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 655-666, 2012

Authors: Kariv-Inbal, Zehavit | Yacobson, Shiri | Berkecz, Robert | Peter, Maria | Janaky, Tamas | Lütjohann, Dieter | Broersen, Laus M. | Hartmann, Tobias | Michaelson, Daniel M.

Article Type: Research Article

Abstract: Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD). Epidemiological studies revealed that consumption of docosahexaenoic acid (DHA: 22 : 6 (ω3)), a major brain polyunsaturated fatty acid, is protective for AD and that elevated cholesterol levels are an AD risk factor. We presently investigated the extent to which the pathological effects of apoE4 in vivo can be prevented by consuming fish oil (DHA) or can be modified by cholesterol. Accordingly, apoE3- and apoE4-targeted replacement mice were subjected, following weaning, to a fish oil diet enriched in DHA and to a cholesterol-containing diet under regular …and enriched environments. Cholesterol metabolism in the hippocampus and the corresponding phospholipid and fatty acid levels were affected by fish oil (DHA) and cholesterol diets and by environmental stimulation. Importantly, cholesterol metabolism and the fatty acid levels were not affected by apoE4. The phospholipid levels were, however, affected by apoE4. This effect was most pronounced in the cholesterol-fed mice and was abolished by the fish oil (DHA) diet. ApoE4 elevated hippocampal intraneuronal amyloid-β levels under regular conditions and lowered them following environmental stimulation, relative to those of the apoE3 mice. ApoE4 also elevated the levels of the presynaptic transporters Vglut and Vgat, and decreased behavioral performance in an object recognition test. Importantly, all of these apoE4 phenotypes were abolished by the fish oil (DHA) diet, whereas the cholesterol diet modified them. These findings suggest that a fish oil (DHA) diet could be used to attenuate the effects of apoE4 in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E4, cholesterol, DHA, GABAergic, glutamatergic

DOI: 10.3233/JAD-2011-111265

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 667-683, 2012

Authors: Fonseca, Maria B. | Nunes, Ana F. | Rodrigues, Cecília M.P.

Article Type: Research Article

Abstract: p63, the structural and functional homologue of p53, is expressed either as a full-length isoform, containing a transactivation (TA) domain (TAp63), or as a truncated isoform, which lacks TA (ΔNp63). Amyloid-β (Aβ) incubation of neuronal cells results in stress-induced cell death through poorly understood mechanisms. We investigated the role of p63 in Aβ-induced stress. Our results show that Aβ-induced apoptosis of rat PC12 neuronal-like cells and primary cortical neurons was associated with stabilization of pro-apoptotic TAp63 and, most importantly, degradation of anti-apoptotic ΔNp63 through a MAPK- and proteasome-dependent mechanism. This was associated with increased c-Jun, and partially modulated by tauroursodeoxycholic …acid. As expected, classic genotoxic insults resulted in c-Jun upregulation and concomitant ΔNp63 reduction. Endogenous and ectopic ΔNp63 expression was also markedly reduced by c-Jun overexpression. Further, Aβ-mediated ΔNp63 degradation occurred in a c-Jun-dependent manner. Downregulation of c-Jun expression by specific c-Jun siRNA abrogated the reduction of ΔNp63 levels following Aβ insult, whereas overexpression of c-Jun led to its degradation. c-Jun significantly decreased ΔNp63 half-life. Together, these findings demonstrate that the abundance of anti-apoptotic ΔNp63 in response to Aβ-induced cell stress is regulated by a c-Jun-dependent mechanism, and highlight the importance of finding novel targets for potential therapeutic intervention. Show more

Keywords: Amyloid-β peptide, apoptosis, c-Jun, ΔNp63, tauroursodeoxycholic acid

DOI: 10.3233/JAD-2011-111547

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 685-694, 2012

Authors: Yamasaki, Takao | Goto, Yoshinobu | Ohyagi, Yasumasa | Monji, Akira | Munetsuna, Shinji | Minohara, Motozumi | Minohara, Katsuko | Kira, Jun-ichi | Kanba, Shigenobu | Tobimatsu, Shozo

Article Type: Research Article

Abstract: Alzheimer's disease (AD) patients have visuospatial deficits due to parietal dorsal stream dysfunction. Two distinct dorsal flows have been proposed: the inferior parietal (ventro-dorsal (v-d)) and superior parietal (dorso-dorsal (d-d)) streams. We aimed to elucidate how the two dorsal streams are altered in patients with amnestic mild cognitive impairment (aMCI) and AD. Thus, the psychophysical threshold measurements and visual event-related potentials (ERPs) were recorded in patients with aMCI and AD, and in healthy old and young adults. The visual stimuli included radial optic flow (OF) derived from the v-d stream and horizontal (HO) motion conveyed from the d-d stream. The …motion thresholds between aMCI patients and old adults were comparable. However, AD patients showed significantly higher motion thresholds for both stimuli compared with other groups. In lower-level ERPs, there were no significant differences in P1 (100 ms) and N1 (130 ms) for both stimuli among the groups. For higher-level ERPs, aMCI patients showed the prolonged latency of OF-specific P200 (v-d origin) and comparable latency of motion-related N170 (V5/MT origin) for both stimuli compared with old adults. In AD patients, both N170 and P200 latencies were significantly prolonged compared with other groups. P200 latency was closely correlated with the Mini-Mental State Examination score. These findings indicate that the v-d function related to OF perception is selectively impaired in aMCI, whereas AD has impairment of the distributed higher-level dorsal stream. Therefore, OF-specific P200 can be useful for detecting early functional changes of the brain in aMCI. Show more

Keywords: Aging, Alzheimer's disease, coherent motion perception, dorsal visual stream, event-related potentials, mild cognitive impairment, optic flow

DOI: 10.3233/JAD-2011-110167

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 695-708, 2012

Authors: Sugihara, Takahiro | Munesue, Seiichi | Yamamoto, Yasuhiko | Sakurai, Shigeru | Akhter, Nasima | Kitamura, Yoji | Shiba, Kazuhiro | Watanabe, Takuo | Yonekura, Hideto | Hayashi, Yasuhiko | Hamada, Jun-ichiro | Yamamoto, Hiroshi

Article Type: Research Article

Abstract: The cell-surface receptor for advanced glycation end-products (RAGE) has been implicated in the development of diabetic vascular complications and Alzheimer's disease. RAGE has been considered to be involved in amyloid-β1-42 (Aβ1-42 ) uptake into brain. In the present study, we demonstrate that endogenous secretory RAGE (esRAGE), a decoy form of RAGE generated by alternative RNA processing, is able to inhibit Aβ1-42 influx into mouse brain. Surface plasmon resonance and competitive binding assays revealed that human Aβ1-42 interacted with human esRAGE within the immunoglobulin V type region. We next examined the uptake and distribution of 125 I-labeled human …Aβ1-42 in various organs and body fluids of newly created mice overexpressing human esRAGE as well as RAGE-null and wild-type (WT) mice. The transition of the 125 I-labeled Aβ1-42 from circulation to brain parenchyma peaked at 30 min after the injection into WT mice, but this was significantly blunted in esRAGE-overexpressing and RAGE-null mice. Significant reduction in 125 I-labeled Aβ1-42 -derived photo-stimulated luminescence were marked in ventricles, cerebral cortex, hippocampus, especially CA1 and CA3 regions, putamen, and thalamus. The results thus suggest the potential of esRAGE in protection against the development of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β1-42, esRAGE, RAGE, transgenic mice

DOI: 10.3233/JAD-2011-110776

Citation: Journal of Alzheimer's Disease, vol. 28, no. 3, pp. 709-720, 2012