Journal of Alzheimer's Disease - Volume 17, issue 4

Authors: Tong, Ming | Neusner, Alexander | Longato, Lisa | Lawton, Margot | Wands, Jack R. | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: The current epidemics of type 2 diabetes mellitus (T2DM), non-alcoholic steatohepatitis (NASH), and Alzheimer's disease (AD) all represent insulin-resistance diseases. Previous studies showed that streptozotocin, a nitrosamine-related compound, causes insulin resistance diseases including, T2DM, NASH, and AD-type neurodegeneration. We hypothesize that chronic human exposure to nitrosamine compounds, which are widely present in processed foods, contributes to the pathogenesis of T2DM, NASH, and AD. Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. (x3) or i.c. (x1) injection, and 2–4 weeks later, they were evaluated for cognitive-motor dysfunction, insulin resistance, and neurodegeneration using behavioral, biochemical, and molecular approaches. NDEA …treatment caused T2DM, NASH, deficits in motor function and spatial learning, and neurodegeneration characterized by insulin resistance and deficiency, lipid peroxidation, cell loss, increased levels of amyloid-β protein precursor/amyloid-β, phospho-tau, and ubiquitin immunoreactivities, and upregulated expression of pro-inflammatory cytokine and pro-ceramide genes, which together promote insulin resistance. In conclusion, environmental and food contaminant exposures to nitrosamines play critical roles in the pathogenesis of major insulin resistance diseases including T2DM, NASH, and AD. Improved detection and prevention of human exposures to nitrosamines will lead to earlier treatments and eventual quelling of these costly and devastating epidemics. Show more

Keywords: Alzheimer's disease, diabetes, environmental toxin, neurodegeneration, nitrosamine, obesity

DOI: 10.3233/JAD-2009-1155

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 827-844, 2009

Authors: Nagababu, Enika | Usatyuk, Peter V. | Enika, Divya | Natarajan, Viswanathan | Rifkind, Joseph M.

Article Type: Research Article

Abstract: Neuronal inflammation is very common in Alzheimer's disease (AD). This inflammation can be caused by infiltration of neutrophils across the blood brain barrier. Endothelial permeability changes are required for the infiltration of high molecular weight components to the brain. Deposition of toxic amyloid-β (Aβ) fibrils in the cerebral vasculature, as well as in brain neurons, has been implicated in the development of AD. This study investigates the effect of Aβ fibrils on the permeability of the endothelium and the mechanism for the observed permeability changes. Aβ1-40 and Aβ1-42 fibrils, but not monomers, were found to increase permeability of …bovine pulmonary arterial endothelial cells in a dose- and time dependent manner as detected by transendothelial electrical resistance. This increase in permeability is only partially (25%) inhibited by catalase and is not associated with an increase in cytosolic Ca+2 or tyrosine phosphorylation. These results indicate that hydrogen peroxide is not the primary mediator for the permeability changes. Treatment of cells with both amyloid fibrils resulted in stress fiber formation, disruption and aggregation of actin filaments, and cellular gap formation. The results of this study reveal that Aβ increases the permeability of endothelium by inducing change in the cytoskeleton network. Show more

Keywords: Alzheimer's disease, amyloid-β, endothelial cells, permeability

DOI: 10.3233/JAD-2009-1104

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 845-854, 2009

Authors: Perneczky, Robert | Wagenpfeil, Stefan | Lunetta, Kathryn L. | Cupples, L. Adrienne | Green, Robert C. | DeCarli, Charles | Farrer, Lindsay A. | Kurz, Alexander

Article Type: Research Article

Abstract: Functional imaging and neuropathological studies suggest that individuals with higher education have better cognitive performance at the same level of brain pathology than less educated subjects. No in vivo studies are available that directly test how education modifies the effect of structural pathology on cognition in Alzheimer's disease (AD). The present study therefore aimed to measure this effect using data from a large multi-center study. 270 patients with AD underwent cognitive testing using the Mini Mental State Examination (MMSE), apolipoprotein E (APOE) genotyping, and cerebral magnetic resonance imaging. A linear regression analysis was used to examine the relation of medial …temporal lobe atrophy (MTA), as a proxy of AD pathology, to MMSE score, adjusting for age, gender, APOE, cerebrovascular disease, ethnicity, education, and disease duration. An interaction term for MTA and education was introduced to test the hypothesis that education modifies the effect of MTA on cognition. There was a significant inverse association between MTA and cognition. Most interestingly, the interaction term between education and MTA was significant suggesting that education modifies the relation of MTA to cognition. At any level of pathology, cognition remained higher for better educated individuals. Show more

Keywords: Alzheimer's disease, cognition, cognitive reserve, dementia, education, hippocampus, magnetic resonance imaging, medial temporal lobe atrophy

DOI: 10.3233/JAD-2009-1117

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 855-862, 2009

Authors: Meyne, Felix | Gloeckner, Sara Friederike | Ciesielczyk, Barbara | Heinemann, Uta | Krasnianski, Anna | Meissner, Bettina | Zerr, Inga

Article Type: Research Article

Abstract: We performed a study on levels of the total prion protein (PrP) in humans affected by different neurological diseases and assessed the influence of several factors such as age, gender, and disease severity on the cerebrospinal fluid PrP levels. PrP-ELISA technique was used to analyze cerebrospinal fluid (CSF) samples. 293 CSF samples of patients with Creutzfeldt-Jakob-disease (CJD), Alzheimer's disease, dementia with Lewy-bodies, Parkinson's disease, multiple sclerosis, cerebral ischemia, generalized epileptic seizures, and meningitis and encephalitis in comparison to controls were analyzed. We found a significant reduction of CSF PrP levels in patients suffering from all neurodegenerative disorders analyzed. This group …exhibited mean PrP values of 164 ng/ml while non-neurodegenerative disorder patients and healthy controls showed PrP levels of 208 ng/ml and 226 ng/ml, respectively. CSF levels correlated with disease severity in CJD, Alzheimer's disease, and dementia with Lewy-bodies. The finding of decreased PrP levels in the CSF of patients not only with CJD but also in other neurodegenerative disorders is intriguing. Age-, gender-, and genetic-specific factors might be involved in the PrPc regulation. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, Creutzfeldt-Jakob-disease, dementia, dementia with Lewy-bodies, disease severity, prion protein, tau

DOI: 10.3233/JAD-2009-1110

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 863-873, 2009

Authors: Haneuse, Sebastien | Larson, Eric | Walker, Rod | Montine, Thomas | Sonnen, Joshua

Article Type: Research Article

Abstract: Current neuropathologic consensus criteria for diagnosis of dementia yield a classification of processes that likely contributed to dementia in that individual. While dementia diagnosis currently relies on clinical criteria, practicing neuropathologists and researchers might benefit from a simple, accurate risk scoring protocol for the neuropathologic diagnosis of dementia. Using 232 consecutive autopsies from the population-based Adult Changes in Thought study, we developed two logistic regression-based risk scoring systems; one solely using neuropathologic measures and a second additionally including demographic information. Inverse-probability weighting was used to adjust for inherent selection bias in autopsy-based studies of dementing illnesses. Both systems displayed high …levels of predictive accuracy; bias-adjusted area-under-the-curve statistics were 0.78 (95% CI 0.71, 0.85) and 0.87 (95% CI 0.83, 0.92), indicating improved performance with the inclusion of demographic characteristics, specifically age and birth cohort information. Application of the combined neuropathlogy/demographic model yielded bias-adjusted sensitivity and specificity of 81% each. In contrast, application of NIA-Reagan criteria yielded sensitivity and specificity of 53% and 84%. Our proposed scoring systems provide neuropathologists with tools to make a diagnosis, and interpret their diagnosis in the light of known sensitivity and specificity estimates. Evaluation in independent samples will be important to verify our findings. Show more

Keywords: Alzheimer's disease, autopsy, dementia, microinfarcts, neuropathology, prediction, selection bias

DOI: 10.3233/JAD-2009-1105

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 875-885, 2009

Authors: Zdanys, Kristina F. | Kleiman, Timothy G. | Zhang, Huiping | Ozbay, Fatih | MacAvoy, Martha G. | Gelernter, Joel | van Dyck, Christopher H.

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that promotes neuronal survival, growth, and differentiation. The role of BDNF in learning and memory suggests that it may also modulate the clinical course of Alzheimer's disease (AD). This study aimed to determine whether BDNF genetic variants are related to premorbid educational attainment, progression of cognitive and functional decline, and associated neuropsychiatric symptoms in AD patients. A sample of AD subjects (N = 341) was genotyped for the BDNF polymorphisms: Val66Met, C270T, and G-712A. Subjects received tests of cognition and daily function at baseline and at multiple subsequent time points. They were also …characterized for the frequency and severity of neuropsychiatric symptoms. There was a significant effect of Val66Met genotype on educational attainment (F = 7.49, df = 2,329, P = 0.00066), with Met/Met homozygotes having significantly lower education than both the Val/Met and Val/Val groups. No association was observed between any BDNF polymorphism and measures of cognitive or functional decline. The T-allele of the C270T polymorphism was associated with a higher prevalence of neuropsychiatric symptoms and specifically with the presence of hallucinations. The effect of the Val66Met polymorphism on premorbid educational attainment is intriguing and should be verified in a larger sample. Show more

Keywords: Activities of daily living, Alzheimer's disease, brain-derived neurotrophic factor, cognition, education, single nucleotide polymorphism

DOI: 10.3233/JAD-2009-1106

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 887-898, 2009

Authors: Panza, Francesco | D'Introno, Alessia | Colacicco, Anna M. | Capurso, Cristiano | Del Parigi, Angelo | Caselli, Richard J. | Frisardi, Vincenza | Scapicchio, Pierluigi | Chiloiro, Roberta | Scafato, Emanuele | Gandin, Claudia | Vendemiale, Gianluigi | Capurso, Antonio | Solfrizzi, Vincenzo

Article Type: Research Article

Abstract: The temporal relationship between depression and cognitive decline has not been extensively investigated in prospective population-based studies, and most of these have only looked in one direction. We estimated the bidirectional temporal relationship between depressive symptoms and cognitive function in older subjects, excluding subjects with a clinical diagnosis of dementia or mild cognitive impairment (MCI). In a total of 2,963 individuals from the Italian Longitudinal Study on Aging, depressive symptoms, global cognitive function, and episodic memory were measured. Dementia, Alzheimer's disease, vascular dementia, and MCI were classified using current clinical criteria. Depressive symptoms at baseline were associated with an accelerated …global cognitive function decline and an accelerated rate of episodic memory delayed recall decline in a 3.5-year follow-up. Finally, an accelerated increase with time of depressive symptoms during the same follow-up period was not associated with global cognitive function and episodic memory (immediate and delayed recall). In older subjects non-cognitively impaired, depressive symptoms at baseline predicted change over time of global cognitive decline and episodic memory delayed recall. Global cognitive function and episodic memory at baseline were not associated with the course of depressive symptoms during the follow-up. Show more

Keywords: Alzheimer's disease, cognitive aging, dementia, depression, memory disorders

DOI: 10.3233/JAD-2009-1111

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 899-911, 2009

Authors: Cente, Martin | Filipcik, Peter | Mandakova, Stanislava | Zilka, Norbert | Krajciova, Gabriela | Novak, Michal

Article Type: Research Article

Abstract: Oxidative stress has been implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). We investigated the effect of a truncated form of the human tau protein in the neurons of transgenic rats. Using electron paramagnetic resonance we observed significantly increased accumulation of ascorbyl free radicals in brains of transgenic animals (up to 1.5-fold increase; P < 0.01). Examination of an in vitro model of cultured rat corticohippocampal neurons revealed that even relatively low level expression of human truncated tau protein (equal to 50% of endogenous tau) induced oxidative stress that resulted in increased depolarization of mitochondria (∼1.2-fold …above control, P < 0.01) and increases in reactive oxygen species (∼1.3-fold above control, P < 0.001). We show that mitochondrial damage-associated oxidative stress is an early event in neurodegeneration. Furthermore, using two common antioxidants (vitamin C and E), we were able significantly eliminate tau-induced elevation of reactive oxygen species. Interestingly, vitamin C was found to be selective in the scavenging activity, suggesting that expression of truncated tau protein preferentially leads to increases in aqueous phase oxidants and free radicals such as hydrogen peroxide and hydroxyl and superoxide radicals. Our results suggest that antioxidant strategies designed to treat AD should focus on elimination of aqueous phase oxidants and free radicals. Show more

Keywords: Antioxidants, oxidative stress, transgenic rat, truncated tau

DOI: 10.3233/JAD-2009-1107

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 913-920, 2009

Authors: Polidori, M. Cristina | Praticó, Domenico | Mangialasche, Francesca | Mariani, Elena | Aust, Olivier | Anlasik, Timur | Mang, Ni | Pientka, Ludger | Stahl, Wilhelm | Sies, Helmut | Mecocci, Patrizia | Nelles, Gereon

Article Type: Research Article

Abstract: A higher daily intake of fruits and vegetables in healthy elderly is associated with an improved antioxidant status in comparison to subjects consuming diets poor in fruits and vegetables, but the impact on cognitive performance is unclear. Healthy community dwellers (45 to 102 years old, n=193) underwent cognitive testing and blood withdrawal for the measurement of antioxidant micronutrients and biomarkers of oxidative stress as well as administration of a food frequency questionnaire to assess the daily intake of fruits and vegetables (high intake HI, low intake LI). Ninety-four subjects of the HI group had significantly higher cognitive test scores, higher …levels of carotenoids, α- and γ-tocopherol as well as lower levels of F2α isoprostanes than the 99 subjects of the LI group. Cognitive scores were directly correlated with blood levels of α-tocopherol and lycopene and negatively correlated with F2α isoprostanes and protein carbonyls. The results were independent of age, gender, body mass index, education, total cholesterol, LDL- and HDL-cholesterol, triglycerides, and albumin. Healthy subjects of any age with a high daily intake of fruits and vegetables have higher antioxidant levels, lower levels of biomarkers of oxidative stress, and better cognitive performance than healthy subjects of any age consuming low amounts of fruits and vegetables. Modification of nutritional habits aimed at increasing intake of fruits and vegetables should be encouraged to lower prevalence of cognitive impairment in later life. Show more

Keywords: Antioxidants, cognitive aging, dementia, isoprostanes, micronutrients, neuropsychology, nutrition, oxidative stress, prevention, vitamins

DOI: 10.3233/JAD-2009-1114

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 921-927, 2009

Authors: Zhou, Xin-Wen | Winblad, Bengt | Guan, Zhizhong | Pei, Jin-Jing

Article Type: Research Article

Abstract: In this study, we investigated how tau phosphorylation is regulated by protein kinase glycogen synthase kinase 3β (GSK3β), protein kinase B (PKB), and protein phosphatase 2A (PP2A) in mouse N2a neuroblastoma cells. Results showed that GSK3β overexpression significantly increased PKB phosphorylation at the S473 site but not the T308 site. Neither GSK3β nor PKB overexpression could reduce the PP2AC phosphorylation at the Y307 site. In contrast, either PKB or GSK3β knockdown could increase PP2A phosphorylation at the Y307 site. PP2AC knockdown increased GSK3β phosphorylation at the S9 site but not at the Y216 site, and PKB phosphorylation at …the T308 site but not at the S473 site. Tau phosphorylation at the S396 site was increased by GSK3β or PKB overexpression. Tau phosphorylation at the S214 site was only induced by PKB overexpression in the study. While GSK3β knockdown decreased tau phosphorylation at the S396 site, PKB knockdown increased tau phosphorylation at both the S396 and S214 sites. PP2AC knockdown decreased tau phosphorylation at the S396 and S214 sites. These findings suggest that tau phosphorylation at the S396 and S214 sites is differentially regulated by GSK3β, PKB, and PP2A in N2a cells. The final phosphorylation state of tau is possibly caused by the synergic action of the three enzymes. Show more

Keywords: Glycogen synthase kinase 3β, protein kinase B, protein phosphatase 2A, tau

DOI: 10.3233/JAD-2009-1113

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 929-937, 2009