Journal of Alzheimer's Disease - Volume 21, issue 3

Authors: Wang, Xiaojuan | Xing, Anfeng | Xu, Changlei | Cai, Qing | Liu, Hong | Li, Liang

Article Type: Research Article

Abstract: Cerebrovascular hypoperfusion occurs prior to the clinical symptoms of Alzheimer's disease (AD) and represents the most accurate indicator predicting whether an individual develops AD at a future time. To study how cerebrovascular hypoperfusion contributes to AD, we induced cerebrovascular hypoperfusion by bilateral carotid occlusion surgery in adult rats and investigated its impacts on spatial memory, synapses, and accumulation of oligomeric amyloid-β. We found progressive spatial memory deficits, as tested by Morris water maze, starting 30 days after occlusion surgery. The memory deficits were accompanied with decrease in synaptic density and alterations of synaptic ultrastructure in the CA1 area of the …hippocampus, as evaluated by electron microscopy. By using immunoelectron microscopy, we also found time-dependent accumulation of oligomeric amyloid-β in the hippocampus, especially in the axonal terminals after chronic cerebrovascular hypoperfusion. Western blot analysis revealed decreased levels of postsynaptic density-95 (PSD-95) and synaptophysin in rat brains after chronic cerebrovascular hypoperfusion. Our findings provide novel insight into the mechanism by which chronic cerebrovascular hypoperfusion contributes to the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, cerebrovascular hypoperfusion, rats spatial memory, synapse

DOI: 10.3233/JAD-2010-100216

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 813-822, 2010

Authors: Zeng, Yan | Zhao, Danyun | Xie, Cui-Wei

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide-induced impairment of hippocampal synaptic plasticity is considered an underlying mechanism for memory loss in the early stages of Alzheimer's disease and its animal models. We previously reported inhibition of long-term potentiation (LTP) and miniature excitatory postsynaptic currents by oligomeric Aβ1–42 at hippocampal synapses. While multiple cellular mechanisms could be involved in Aβ-induced synaptic dysfunction, blockade of activity-dependent autophosphorylation of Ca2+ and calmodulin-dependent protein kinase II (CaMKII) appeared to be a major component of Aβ action in our studies. The present study further tested this hypothesis and examined the therapeutic potential of trkB receptor-acting neurotrophins in …rescuing Aβ-induced synaptic and signaling impairments. As expected, treatment of rat hippocampal slices with Aβ1–42 significantly reduced LTP in the Schaffer collateral-CA1 pathway and dentate medial perforant path. LTP-associated CaMKII activation and AMPA receptor phosphorylation were blocked by Aβ1–42 at the same concentration that inhibited LTP. Aβ-induced LTP impairment, however, was prevented when slices were co-treated with neurotrophin 4 (NT4). Western blotting and immunohistochemical analyses confirmed that treatment with NT4 or brain-derived neurotrophic factor, another trkB-acting neurotrophin, could oppose Aβ action, enhancing autophosphorylation of CaMKII, and AMPA receptor phosphorylation at a CaMKII-dependent site. These findings support the view that CaMKII is a key synaptic target of Aβ toxicity as well as a potential therapeutic site of neurotrophins for Alzheimer's disease. Show more

Keywords: Amyloid-β, calcium and calmodulin-dependent protein kinase II, hippocampus, long-term potentiation, neurotrophins

DOI: 10.3233/JAD-2010-100264

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 823-831, 2010

Authors: Kauwe, John S.K. | Cruchaga, Carlos | Bertelsen, Sarah | Mayo, Kevin | Latu, Wayne | Nowotny, Petra | Hinrichs, Anthony L. | Fagan, Anne M. | Holtzman, David M. | Alzheimer's Disease Neuroimaging Initiative, | Goate, Alison M.

Article Type: Research Article

Abstract: Recent large-scale genetic studies of late-onset Alzheimer's disease have identified risk variants in CALHM1, GAB2, and SORL1. The mechanisms by which these genes might modulate risk are not definitively known. CALHM1 and SORL1 may alter amyloid-β (Aβ) levels and GAB2 may influence phosphorylation of the tau protein. In this study we have analyzed disease associated genetic variants in each of these genes for association with cerebrospinal fluid (CSF) Aβ or tau levels in 602 samples from two independent CSF series. We failed to detect association between CSF Aβ42 levels and single nucleotide polymorphisms in SORL1 despite substantial statistical power …to detect association. While we also failed to detect association between variants in GAB2 and CSF tau levels, power to detect this association was limited. Finally, our data suggest that the minor allele of rs2986017, in CALHM1, is marginally associated with CSF Aβ42 levels. This association is consistent with previous reports that this non-synonymous coding substitution results in increased Aβ levels in vitro and provides support for an Aβ-related mechanism for modulating risk for Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid, association, CALHM1, endophenotypes, GAB2, genetics, SORL1, tau

DOI: 10.3233/JAD-2010-091711

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 833-842, 2010

Authors: Cummings, Jeffrey | Jones, Roy | Wilkinson, David | Lopez, Oscar | Gauthier, Serge | Waldemar, Gunhild | Zhang, Richard | Xu, Yikang | Sun, Yijun | Richardson, Sharon | Mackell, Joan

Article Type: Research Article

Abstract: To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N = 904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1–5, 6–9, 10–12 and 13–17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total …scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6–9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17–0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful. Show more

Keywords: Alzheimer's disease, cognition, donepezil, functional outcome, global outcome, placebo-controlled, pooled data analysis, severe Alzheimer's disease, Severe Impairment Battery

DOI: 10.3233/JAD-2010-100078

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 843-851, 2010

Authors: Roberts, Rosebud O. | Cerhan, James R. | Geda, Yonas E. | Knopman, David S. | Cha, Ruth H. | Christianson, Teresa J.H. | Pankratz, V. Shane | Ivnik, Robert J. | O'Connor, Helen M. | Petersen, Ronald C.

Article Type: Research Article

Abstract: Mono- and polyunsaturated fatty acids (MUFA, PUFA) have been associated with a reduced risk of dementia. The association of these fatty acids with mild cognitive impairment (MCI) is not fully established. The objective of the study was to investigate the cross-sectional association of dietary fatty acids with MCI in a population-based sample. Participants aged ⩾ 70 years on October 1, 2004, were evaluated using the Clinical Dementia Rating Scale (participant and informant), a neurological evaluation, and neuropsychological testing. A panel of nurses, physicians, and neuropsychologists reviewed the data for each participant in order to establish a diagnosis of MCI, normal …cognition, or dementia by consensus. Participants also completed a 128-item food-frequency questionnaire. Among 1,233 non-demented subjects, 163 (13.2%) had MCI. The odds ratio (OR) of MCI decreased with increasing PUFA and MUFA intake. Compared to the lowest tertile, the OR (95% confidence interval) for the upper tertiles were 0.44 (0.29–0.66; p for trend = 0.0004) for total PUFA; 0.44 (0.30–0.67; p for trend = 0.0004) for omega-6 fatty acids; 0.62 (0.42–0.91; p for trend = 0.012) for omega-3 fatty acids; and 0.56 (0.38–0.83; p for trend = 0.01) for (MUFA+PUFA):saturated fatty acid ratio after adjustment for age, sex, number of years of education, and caloric intake. In this study, higher intake of PUFA and MUFA was associated with a reduced likelihood of MCI among elderly persons in the population-based setting. Show more

Keywords: Cross-sectional studies, dietary fats, mild cognitive impairment, monounsaturated fatty acids, polyunsaturated fatty acids, population-based

DOI: 10.3233/JAD-2010-091597

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 853-865, 2010

Authors: Panza, Francesco | Frisardi, Vincenza | Seripa, Davide | Imbimbo, Bruno P. | Pilotto, Alberto | Solfrizzi, Vincenzo

Article Type: Article Commentary

Abstract: An increasing body of epidemiological evidence suggested that elevated saturated fatty acids could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI). Furthermore, a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. In the present article, on the basis of increasing body of evidence from cross-sectional and longitudinal population-based studies, we discussed the issue of the possible impact of dietary PUFA (both n-6 and n-3) on ARCD, MCI, and Alzheimer's disease.

Keywords: Alzheimer's disease, dementia, fatty acids, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-2010-100777

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 867-870, 2010

Authors: Woodard, John L. | Seidenberg, Michael | Nielson, Kristy A. | Smith, J. Carson | Antuono, Piero | Durgerian, Sally | Guidotti, Leslie | Zhang, Qi | Butts, Alissa | Hantke, Nathan | Lancaster, Melissa | Rao, Stephen M.

Article Type: Research Article

Abstract: Few studies have examined the extent to which structural and functional MRI, alone and in combination with genetic biomarkers, can predict future cognitive decline in asymptomatic elders. This prospective study evaluated individual and combined contributions of demographic information, genetic risk, hippocampal volume, and fMRI activation for predicting cognitive decline after an 18-month retest interval. Standardized neuropsychological testing, an fMRI semantic memory task (famous name discrimination), and structural MRI (sMRI) were performed on 78 healthy elders (73% female; mean age = 73 years, range = 65 to 88 years). Positive family history of dementia and presence of one or both apolipoprotein …E (APOE) ε4 alleles occurred in 51.3% and 33.3% of the sample, respectively. Hippocampal volumes were traced from sMRI scans. At follow-up, all participants underwent a repeat neuropsychological examination. At 18 months, 27 participants (34.6%) declined by at least 1 SD on one of three neuropsychological measures. Using logistic regression, demographic variables (age, years of education, gender) and family history of dementia did not predict future cognitive decline. Greater fMRI activity, absence of an APOE ε4 allele, and larger hippocampal volume were associated with reduced likelihood of cognitive decline. The most effective combination of predictors involved fMRI brain activity and APOE ε4 status. Brain activity measured from task-activated fMRI, in combination with APOE ε4 status, was successful in identifying cognitively intact individuals at greatest risk for developing cognitive decline over a relatively brief time period. These results have implications for enriching prevention clinical trials designed to slow AD progression. Show more

Keywords: Aging, apolipoprotein E, cognitive decline, fMRI, hippocampal volume, neuroimaging, memory

DOI: 10.3233/JAD-2010-091693

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 871-885, 2010

Authors: Luo, Jinhua | Grammas, Paula

Article Type: Research Article

Abstract: The vasoactive protein endothelin-1 (ET-1) is produced by vascular endothelial cells and participates in the regulation of vascular inflammation. We have previously documented that the cerebral microvasculature is a source of inflammatory proteins and a likely contributor to the pathogenesis of Alzheimer's disease (AD). In this study, we (a) compare expression of ET-1 in brain microvessels isolated from AD and control brains; (b) determine thrombin regulation of ET-1 synthesis and release in brain endothelial cells; and (c) assess the effects of ET-1 on neuronal viability in vitro. Western blot analysis indicates a significantly higher level of ET-1 in AD vessels …compared to vessels from age-matched controls. ET-1 expression and secretion are both induced by the inflammatory and neurotoxic protein thrombin. Pretreatment of neuronal cultures with ET-1 significantly increases neuronal survival when cells are challenged with oxidative stress (H2 O2 ) or thrombin. The protective effect of ET-1 is blocked by incubation with an inhibitor of the c-Jun kinase (JNK) cascade. These data demonstrate that in the brain microvasculature dysfunctional or stressed endothelial cells express ET-1 and that this protein promotes the survival of brain neurons exposed to injury. Show more

Keywords: Endothelin-1, microvessels, neuroprotective, thrombin

DOI: 10.3233/JAD-2010-091486

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 887-896, 2010

Authors: Rovelet-Lecrux, Anne | Hannequin, Didier | Guillin, Olivier | Legallic, Solenn | Jurici, Snejana | Wallon, David | Frebourg, Thierry | Campion, Dominique

Article Type: Research Article

Abstract: Microduplications at 17q21.31 have recently been reported in children with mental retardation, autism spectrum disorders and/or dysmorphic features, as well as in a single schizophrenic patient. This rearrangement encompasses the microtubule associated protein tau (MAPT) gene, mutations of which are a major cause of frontotemporal lobar degeneration (FTLD). However, no 17q21.31 microduplication has been so far identified in this condition. We screened chromosomal rearrangements in FTLD patients using quantitative multiplex PCR of short fluorescent fragments and high resolution array CGH. We found a 439-kb microduplication at the 17q21.31 locus encompassing the MAPT, IMP5, CRHR1, and STH genes in the index …case of a family in which three patients have developed a FTLD phenotype associated with marked memory impairment. None of these patients had mental retardation or dysmorphic features. Since no pathological examination was available, we are not certain that this case corresponds to a FTLD with neuronal and glial tau inclusions (FTLD-tau), and we cannot exclude that any other gene included in the rearrangement might be responsible for the neurodegenerative process. However, the clinical phenotype of the three patients is functionally consistent with the regional pattern of lesions previously reported in mice overexpressing human tau. Show more

Keywords: Dementia, frontotemporal, gene duplication, MAPT, schizophrenia

DOI: 10.3233/JAD-2010-100441

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 897-902, 2010

Authors: Quinn, Joseph F. | Harris, Christopher J. | Cobb, Katherine E. | Domes, Christopher | Ralle, Martina | Brewer, George | Wadsworth, Teri L.

Article Type: Research Article

Abstract: There is increasing evidence for the crucial role of metals in the pathology of Alzheimer's disease. Both the aggregation and neurotoxicity of amyloid-β are dependent on the presence of copper. This study investigated the ability of the copper-complexing drug tetrathiomolybdate to reduce amyloid-β pathology and spatial memory impairment in both a prevention and a treatment paradigm in the Tg2576 mouse model of Alzheimer's disease. Tetrathiomolybdate treatment lowered brain copper and reduced amyloid-β levels in the prevention paradigm, but not in the treatment paradigm. Our data suggests that controlled lowering of systemic copper may achieve anti-amyloid effects if initiated early in …the disease process. Show more

Keywords: Alzheimer's disease, amyloid, copper, tetrathiomolybdate, Tg2576

DOI: 10.3233/JAD-2010-100408

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 903-914, 2010