Journal of Alzheimer's Disease - Volume 29, issue 2

Authors: Venkataramani, Vivek | Wirths, Oliver | Budka, Herbert | Härtig, Wolfgang | Kovacs, Gabor G. | Bayer, Thomas A.

Article Type: Research Article

Abstract: Recent evidence suggests that soluble oligomeric amyloid-β (Aβ) assemblies are critically involved in the pathogenesis of Alzheimer's disease (AD). We have generated a conformation-dependent monoclonal antibody (9D5) that selectively recognizes low-molecular weight AβpE3 oligomers, and demonstrated its diagnostic and therapeutic potential. Here, we further characterize the specificity of this antibody by evaluating a spectrum of neurodegeneration-related protein deposits for cross-reactivity, and by comparing the staining pattern of 9D5 with a generic Aβ antibody that targets a linear epitope (mAb NT244), and with another conformation-dependent Aβ antibody that selectively labels amyloid fibrils of various molecular weights (pAb OC). The 9D5 …antibody does not cross-react with other aggregated protein deposits in brains of progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal lobar degeneration or amyotrophic lateral sclerosis with TDP-43 inclusions, Creutzfeldt-Jakob disease, and vessel changes in Binswanger encephalopathy, demonstrating the specificity of 9D5 for Aβ deposits. While NT244 and OC showed a comparable plaque load, 9D5 detected only approximately 15% of the total Aβ plaque load in the entorhinal cortex, the CA1 region, and the temporal neocortex. Our study further supports a possible therapeutic advantage of 9D5 by the highly specific recognition of an epitope found only in oligomeric assemblies of AβpE3 of AD patients. Moreover, selective binding to only a pathogenetically relevant fraction of Aβ deposits serves as rationale for passive immunization with 9D5-derivatives by limiting potential side effects of vaccination due to dissolvement of existing amyloid deposits. Show more

Keywords: Alzheimer's disease, amyloid, antibodies, conformation-dependent oligomers, immunohistochemistry, N-truncated Abeta, neurodegenerative disease, proteinopathy, pyroglutamate

DOI: 10.3233/JAD-2011-111379

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 361-371, 2012

Authors: Kimura, Akio | Sakurai, Takeo | Yamada, Megumi | Koumura, Akihiro | Hayashi, Yuichi | Tanaka, Yuji | Hozumi, Isao | Ohtaki, Hirofumi | Chousa, Mitsuhiro | Takemura, Masao | Seishima, Mitsuru | Inuzuka, Takashi

Article Type: Research Article

Abstract: Recent studies suggest that microvascular abnormalities are involved in pathology and progression of Alzheimer's disease. The purpose of this study was to examine the presence of antibodies against cerebral microvascular endothelial cells specific for Alzheimer's disease, and to evaluate the association of these antibodies with cognitive impairment. The study included patients with Alzheimer's disease (age ≥60 years; 24 patients), control subjects without neurological diseases (age ≥60 years; 19 subjects), patients with multiple sclerosis (all ages; 17 patients), and healthy control subjects (age <40 years; 18 subjects). Serum was analyzed with 2-dimensional electrophoresis and Western blot, with cultured human brain microvascular …endothelial cells as the antigen source. The anti-Tom40 antibody was identified significantly more frequently in patients with Alzheimer's disease than control subjects or patients with multiple sclerosis. In patients with Alzheimer's disease, the mean scores for the Mini-Mental State Examination were significantly lower for patients who were positive for anti-Tom40 antibody than those who were negative for anti-Tom40 antibody. In summary, the anti-Tom40 antibody is significantly associated with cognitive impairment in patients with Alzheimer's disease. Show more

Keywords: Antigen, cognition, dementia, endothelial cell, mitochondrion, pathogenesis

DOI: 10.3233/JAD-2011-111343

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 373-377, 2012

Authors: Peng, Ying | Hu, Yanli | Xu, Shaofeng | Li, Pingping | Li, Jiang | Lu, Li | Yang, Hongyan | Feng, Nan | Wang, Ling | Wang, Xiaoliang

Article Type: Research Article

Abstract: L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been shown to have neuroprotective effects on cerebral ischemic, vascular dementia and amyloid-β (Aβ)-induced animal models by inhibiting oxidative injury, neuronal apoptosis and glial activation, regulating amyloid-β protein precursor (AβPP) processing and reducing Aβ generation. The aim of the present study was to examine the effect of L-NBP on learning and memory in AβPP and presenilin 1 (PS1) double-transgenic AD mouse model (AβPP/PS1) and the mechanisms of L-NBP in reducing Aβ accumulation and tau phosphorylation. Twelve-month old AβPP/PS1 mice were given 15 mg/kg L-NBP by oral gavage …for 3 months. L-NBP treatment significantly improved the spatial learning and memory deficits compared to the vehicle-treated AβPP/PS1 mice, whereas L-NBP treatment had no effect on cerebral Aβ plaque deposition and Aβ levels in brain homogenates. However, we found an L-NBP-induced reduction of tau hyperphosphorylation at Ser199, Thr205, Ser396, and Ser404 sites in AβPP/PS1 mice. Additionally, the expressions of cyclin-dependent kinase and glycogen synthase kinase 3β, the most important kinases involved in tau phosphorylation, were markedly decreased by L-NBP treatment. The effects of L-NBP on decreasing tau phosphorylation and kinases activations were further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human AβPP695 (SK-N-SH AβPPwt). L-NBP shows promising candidate of multi-target neuronal protective agent for the treatment of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, CDK-5, GSK-3β, L-3-n-butylphthalide, tau

DOI: 10.3233/JAD-2011-111577

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 379-391, 2012

Authors: Caracciolo, Barbara | Gatz, Margaret | Xu, Weili | Pedersen, Nancy L. | Fratiglioni, Laura

Article Type: Research Article

Abstract: We report the prevalence of subjective cognitive impairment (SCI) and cognitive impairment no dementia (CIND), their socio-demographic profile, and the contribution of genetic background and shared familial environment to SCI and CIND. Subjects were 11,926 dementia-free twin individuals aged ≥65 from the Swedish Twin Registry. SCI was defined as subjective complaint of cognitive change without objective cognitive impairment and CIND was defined according to current criteria. Overall prevalence rates of SCI and CIND were 39% (95% CI 38-39%) and 25% (95% CI 24-25%). In multivariate GEE models, both SCI and CIND were older compared with people without any cognitive impairment. …CIND were also less educated, more likely to be unmarried and to have lower socioeconomic status (SES). SCI individuals differed from persons with CIND as they were older, more educated, more likely to be married, and to have higher SES. Co-twin control analysis, which corrects for common genetic and shared environmental background, confirmed the association of low education with CIND. Probandwise concordance for SCI and CIND was 63% and 52% in monozygotic twins, 63% and 50% in dizygotic same-sex twins, and 42% and 29% in dizygotic unlike-sex twins. Tetrachoric correlations showed no significant differences between monozygotic and dizygotic same-sex twins. We conclude that subjective and objective cognitive impairment are both highly prevalent among nondemented elderly yet have distinct sociodemographic profiles. Shared environmental influences rather than genetic background play a role in the occurrence of SCI and CIND. Show more

Keywords: Cognitive impairment no dementia, concordance, population-based, prevalence, socio-demographic, subjective cognitive impairment, twin study

DOI: 10.3233/JAD-2011-111904

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 393-403, 2012

Authors: Clerx, Lies | Visser, Pieter Jelle | Verhey, Frans | Aalten, Pauline

Article Type: Research Article

Abstract: The aim of the present study is to evaluate the diagnostic value of diffusion tensor imaging (DTI) for early Alzheimer's disease (AD) in comparison to widely accepted medial temporal lobe (MTL) atrophy measurements. A systematic literature research was performed into DTI and MTL atrophy in AD and mild cognitive impairment (MCI). We included seventy-six studies on MTL atrophy including 8,122 subjects and fifty-five DTI studies including 2,791 subjects. Outcome measure was the effect size (ES) expressed as Hedges g. In volumetric studies, atrophy of the MTL significantly differentiated between AD and controls (ES 1.32–1.98) and MCI and controls (ES 0.61–1.46). …In DTI-Fractional anisotropy (FA) studies, the total cingulum differentiated best between AD and controls (ES = 1.73) and the parahippocampal cingulum between MCI and controls (ES = 0.97). In DTI-Mean diffusivity (MD) studies, the hippocampus differentiated best between AD and controls (ES = −1.17) and between MCI and controls (ES = −1.00). We can conclude that in general, the ES of volumetric MTL atrophy measurements was equal or larger than that of DTI measurements. However, for the comparison between controls and MCI-patients, ES of hippocampal MD was larger than ES of hippocampal volume. Furthermore, it seems that MD values have somewhat more discriminative power than FA values with higher ES in the frontal, parietal, occipital and temporal lobe. Show more

Keywords: Aging, Alzheimer's disease, diffusion tensor imaging, hippocampus, MRI

DOI: 10.3233/JAD-2011-110797

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 405-429, 2012

Authors: Afgin, Anne E. | Massarwa, Magda | Schechtman, Edna | Israeli-Korn, Simon D. | Strugatsky, Rosa | Abuful, Amin | Farrer, Lindsay A. | Friedland, Robert P. | Inzelberg, Rivka

Article Type: Research Article

Abstract: The prevalence of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been well been studied in Arab populations. In a door-to-door study of all residents aged ≥ 65 years in Wadi-Ara, an Arab community in northern Israel, we estimated the prevalence of AD, MCI, and the risk of conversion to AD. Subjects were classified as cognitively normal, MCI, AD, or other based on neurological and cognitive examination (in Arabic). MCI subjects were re-examined (interval ≥ 1 year) to determine conversion to AD and contributions of age, gender, and education to the probability of conversion. Of the 944 participants …(96.6% of those approached; 49.4% men), 92 (9.8%) had AD. An unusually high prevalence of MCI (n = 303, 32.1%) was observed. Since the majority of women (77.2%) had no schooling, we estimated the effect of gender on the risk of AD and MCI among subjects without schooling and of school years among men. Among subjects with no schooling (n = 452), age (p = 0.02) and female gender (p < 0.0001) were significant predictors of AD, whereas risk of MCI increased only with age (p = 0.0001). Among men (n = 318), age increased the risk (p < 0.0001), school years reduced the risk of AD (p = 0.039) and similarly for MCI [age (p = 0.0001); school years (p = 0.0007)]. Age (p = 0.013), but not gender or school years, was a significant predictor of conversion from MCI to AD (annual rate 5.7%). The prevalence of MCI and AD are unusually high in Wadi Ara, while the rate of conversion from MCI to AD is low. Yet unidentified genetic factors might underlie this observation. Show more

Keywords: Aging, Alzheimer's disease, Arab, mild cognitive impairment, neuroepidemiology, sprevalence, risk factors

DOI: 10.3233/JAD-2011-111667

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 431-439, 2012

Authors: Lee, Yen-Ti | Pai, Ming-Chyi

Article Type: Research Article

Abstract: Many community-residing patients with Alzheimer's disease (AD) have way-finding problems, particularly at twilight or on rainy days. In an attempt to understand the mechanism, we prepared pictures of street scenes, including 8 personally familiar and 8 unfamiliar, divided into Low Spatial Frequency (LSF) and Low Luminance (LL) conditions to simulate foggy or rainy days and nighttime. Each picture was presented from the most difficult (level 10) to the easiest (level 1). The participants, including 20 very mild AD patients and 20 normal controls (NC) with equal basic visual acuity, were asked to judge whether a picture was familiar or not …and to describe how they came to that conclusion. The accuracy of familiar scene recognition was measured by the number of pictures successfully recognized and the ability thereof by the level needed. Compared with NC, AD patients showed poorer accuracy (2.7 ± 0.2 versus 3.6 ± 0.1, mean ± SEM, p = 0.003 under LSF; 2.8 ± 0.2 versus 3.8 ± 0.1, p = 0.001 under LL) and poorer ability (2.2 ± 0.4 versus 4.3 ± 0.4 p = 0.000 under LSF; 2.9 ± 0.3 versus 5.2 ± 0.5, p = 0.000 under LL) for both conditions. The AD patients used a global element to help judge when personally familiar scenes were displayed, which was the method NC usually adopted when presented with novel scenes. In summary, this study demonstrated poorer recognition ability in very mild AD patients when personally familiar street scenes were displayed, and the underlying mechanisms may include impaired visual search performance and efficiency. The deficits also reflect their difficulty in real life situations when their familiar environments become blurred or dark. Show more

Keywords: Familiar, foggy, nighttime, scene recognition, visual search

DOI: 10.3233/JAD-2011-111601

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 441-448, 2012

Authors: Tharp, William G. | Lee, Yong-Ho | Greene, Shane M. | Vincellete, Elise | Beach, Thomas G. | Pratley, Richard E.

Article Type: Research Article

Abstract: Enzymatic cleavage of amyloid-β protein precursor (AβPP) produces amyloid-β (Aβ) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AβPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AβPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AβPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AβPP and all three major isoforms (AβPP695, AβPP751, and …AβPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AβPP and AβPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AβPP751 and AβPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AβPP695 (p = 0.051) and increased percentage AβPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AβPP and AβPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AβPP isoform transcripts by real-time PCR and confirm previous studies showing altered AβPP isoform expression patterns in AD. Show more

Keywords: Alternative splicing, Alzheimer's disease (AD), amyloid-β (Aβ), amyloid-β protein precursor (AβPP), dementia, kunitz, polymerase chain reaction

DOI: 10.3233/JAD-2011-111337

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 449-457, 2012

Authors: Wilkinson, David | Fox, Nick C. | Barkhof, Frederik | Phul, Ravinder | Lemming, Ole | Scheltens, Philip | for the Study 10112 investigators

Article Type: Research Article

Abstract: The primary objective of this study was to evaluate the rate of total brain atrophy (TBA) with serial magnetic resonance imaging (MRI), using the Brain Boundary Shift Integral (BBSI), in patients with probable Alzheimer's disease (AD) over the course of 52 weeks of treatment with memantine or placebo. This was a multi-national, randomized, double-blind, placebo-controlled, fixed-dose 1-year study. Patients were randomized (1 : 1) to treatment with placebo or memantine. Patients randomized to memantine were up-titrated to the target dose of 20 mg/day over 4 weeks. MRI scans were collected at screening and at Weeks 4, 42, and 52. Secondary …efficacy assessments included several cognitive and behavioral scales. 518 patients were screened, 278 patients were randomized, and 217 patients completed the study. In the primary efficacy analysis, the differences in TBA rates between memantine (15.2 mL/year) and placebo (15.3 mL/year) were not statistically significant (−0.04 mL/year [(95% CI: −2.60, 2.52), p = 0.98]). There was a statistically significant correlation between change in TBA and change in most cognitive and behavioral scale scores. Patients who were not treated with acetyl cholinesterase inhibitors (AChEIs) showed a significantly lower TBA rate than patients treated with AChEIs. Memantine had a placebo-level incidence of adverse events. There were no statistically significant differences between memantine and placebo in total brain or hippocampal atrophy rates in patients with probable AD treated for 1 year. The biological relevance of cerebral atrophy was supported by a significant correlation between rate of atrophy and decline in cognitive and behavioral outcomes. Show more

Keywords: Acetyl cholinesterase inhibitors, behavior, cognition, memantine, MRI, placebo, total brain atrophy

DOI: 10.3233/JAD-2011-111616

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 459-469, 2012

Authors: Giustiniani, Julien | Sineus, Marlène | Sardin, Elodie | Dounane, Omar | Panchal, Maï | Sazdovitch, Véronique | Duyckaerts, Charles | Chambraud, Béatrice | Baulieu, Etienne-Emile

Article Type: Research Article

Abstract: Human neurodegenerative diseases characterized by abnormal intraneuronal inclusions of the tau protein, or “tauopathies”, include Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy, corticobasal degeneration as well as fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). Several abnormalities of tau may contribute to the pathological processes, yet the mechanisms involved in tau cellular toxicity remain unclear. Previously, we demonstrated an interaction between various isoforms of tau and the immunophilin FKBP52 (FK506-Binding Protein), suggesting a direct involvement of FKBP52 in tau function. Here we analyze the expression of FKBP52 in human brains of patients with different tauopathies, including AD. Immunohistofluorescence …studies carried out on cerebral cortex in different tauopathies reveal that FKBP52 is not sequestered by filamentous tau inclusions while FKBP52 is colocalized with tau in the control case brains. We found that FKBP52 expression level is abnormally low in frontal cortex of AD and FTDP-17 brains, as compared to controls, despite no alteration in the FKBP52 mRNA expression level. The possible involvement of FKBP52 in pathological tau expression/function is discussed. Show more

Keywords: Alzheimer's disease, FKBP52, frontal cortex, frontotemporal dementia with Parkinsonism, immunophilins, tau, tauopathies

DOI: 10.3233/JAD-2011-111895

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 471-483, 2012