Journal of Alzheimer's Disease - Volume 33, issue 3

Authors: Beaufils, Emilie | Dufour-Rainfray, Diane | Hommet, Caroline | Brault, Florence | Cottier, Jean-Philippe | Ribeiro, Maria Joao | Mondon, Karl | Guilloteau, Denis

Article Type: Research Article

Abstract: Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuo-perceptual dysfunction and praxis declines. This syndrome is related to several underlying diseases, including Alzheimer's disease (AD), sometimes involving an amyloidogenic process. The aims of the study were to 1) define cerebrospinal fluid (CSF) biomarker profiles in PCA patients compared to AD patients and 2) explore the amyloidogenic process through the Aβ42 /Aβ40 ratio in PCA patients to elucidate the underlying disease in vivo. CSF biomarker analysis (t-tau, p-tau, Aβ42 , and Aβ42 /Aβ40 ratio) and neuropsychological examination were performed in 22 PCA patients and compared with those of …age-matched AD patients. Associated clinical neurological signs were investigated (e.g., extrapyramidal motor signs, myoclonus). CSF biomarker profiles did not differ significantly between the PCA and AD groups; 82% of patients with PCA fulfilled the biological criteria for typical AD with abnormal levels of the three markers and 18% of PCA patients presented atypical CSF profiles. All PCA patients with associated clinical neurological signs presented typical AD CSF profiles. The clinical presentations of these patients were similar to other PCA subjects. The Aβ42 /Aβ40 ratio for all PCA patients, including those with atypical CSF profiles, was decreased. Most PCA syndromes were associated with CSF biomarkers suggestive of AD, even in cases with associated clinical neurological signs. The amyloidogenic process was confirmed by the decreased Aβ42 /Aβ40 ratio for all patients. This analysis avoids misdiagnosis in the presence of physiologically high or low amyloid peptide production rates and provides information in vivo to improve understanding of the underlying disease in PCA. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarker, cerebrospinal fluid, posterior cortical atrophy, tau

DOI: 10.3233/JAD-2012-121267

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 775-780, 2013

Authors: Girard, Stéphane D. | Baranger, Kévin | Gauthier, Cyrielle | Jacquet, Marlyse | Bernard, Anne | Escoffier, Guy | Marchetti, Evelyne | Khrestchatisky, Michel | Rivera, Santiago | Roman, François S.

Article Type: Research Article

Abstract: The frontal cortex is a brain structure that plays an important role in cognition and is known to be affected in Alzheimer's disease (AD) in humans. Over the past years, transgenic mouse models have been generated to recapitulate the main features of this disease, including cognitive impairments. This study investigates frontal cortex dependent learning abilities in one of the most early-onset transgenic murine model of AD, the 5XFAD mice. We compared frontal performance of 2-, 4-, and 6-month-old 5XFAD mice with their wild-type littermates using a newly developed automated device, the olfactory H-maze, in which mice have to discover three …different rules consecutively according to the delayed reaction paradigm. We report early cognitive deficits related to frontal cortex appearing in 4-month-old 5XFAD mice before hippocampal-dependent learning and memory impairment, in relation with neuropathologic processes such as strong gliosis and emerging amyloid plaques. The present results demonstrate that the olfactory H-maze is a very sensitive and simple experimental paradigm that allows assessment of frontal functions in transgenic mice and should be useful to test pre-clinical therapeutic approaches to alter the course of AD. Show more

Keywords: Alzheimer's disease, amyloid plaques, delayed tasks, frontal association cortex, gliosis, mouse model, olfactory H-maze, transgenic

DOI: 10.3233/JAD-2012-120982

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 781-796, 2013

Authors: Westmark, Cara J. | Westmark, Pamela R. | Malter, James S.

Article Type: Research Article

Abstract: Seizures are a common phenotype in many neurological disorders including Alzheimer's disease, Down syndrome, and fragile X syndrome. Mouse models of these disorders overexpress amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) and are highly susceptible to audiogenic-induced seizures (AGS). We observed decreased AGS in these mice fed a casein-based, purified diet (D07030301) as opposed to a standard soy protein-containing, non-purified diet (Purina 5015). Our objective in this manuscript was to determine if soy protein, and in particular soy isoflavones, in the Purina 5015 were contributing to the seizure phenotype. Wild running, AGS, and death rates were assessed in juvenile mice …fed Purina 5015, D07030301, D07030301 containing soy protein, or D07030301 supplemented with individual isoflavones (750 mg/kg daidzein or genistein). A short treatment (3 days) with Purina 5015 induced wild running and AGS in Alzheimer's disease mice. A 3-day treatment with daidzein-supplemented diet, but not genistein, induced wild running in wild type mice. To understand the mechanism underlying daidzein activity, we assessed dendritic AβPP expression in primary, cultured, wild type neurons treated with daidzein or genistein. In vitro, daidzein significantly increased dendritic AβPP. Thus, the soy isoflavone daidzein recapitulated seizure induction in vivo and altered AβPP expression in vitro. These results have important implications for individuals on soy-based diets as well as for rodent model research. Show more

Keywords: Amyloid-β, amyloid β-protein precursor, daidzein, isoflavone, seizure, soy

DOI: 10.3233/JAD-2012-121426

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 797-805, 2013

Authors: Le Bastard, Nathalie | Aerts, Laetitia | Sleegers, Kristel | Martin, Jean-Jacques | Van Broeckhoven, Christine | De Deyn, Peter Paul | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: The current treatment for Alzheimer's disease (AD) is purely symptomatic, but medications interfering with underlying pathophysiological processes are being developed. To evaluate a possible disease-modifying effect, cerebrospinal fluid (CSF) biomarkers with a direct link to the underlying pathophysiology, such as amyloid-β1-42 (Aβ1-42 ), total tau protein (T-tau), and hyperphosphorylated tau (P-tau181P ), may play an important role. If intra-individual fluctuations in biomarker levels are small, the difference between two samples could serve as a pharmacodynamic measure. The aim of this study was to evaluate the longitudinal stability of CSF Aβ1-42 , T-tau, and P-tau181P levels in AD patients …and control subjects. Serial CSF samples of 28 AD patients and 23 controls with a minimum time interval of 30 days were included in this study. Serial CSF samples from 10 progressive patients (7 mild cognitive impairment (MCI) patients and 3 controls progressing to MCI or AD) were also analyzed. Intra-individual CSF Aβ1-42 and P-tau181P levels were stable in AD and controls. Intra-individual CSF T-tau levels differed significantly in AD patients, but not in controls. Change in biomarker concentrations per time unit was also significant between groups, but not within groups. The difference in biomarker levels in samples from progressive patients was not significant. In conclusion, CSF levels of Aβ1-42 , T-tau, and P-tau181P are relatively stable over time. Only T-tau increased in AD patients in comparison to controls, which does not preclude its use as a diagnostic marker, nor as a potential pharmacodynamic marker. Show more

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, intra-individual variation, longitudinal sampling

DOI: 10.3233/JAD-2012-110029

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 807-822, 2013

Authors: López, Natividad | Tormo, Consuelo | De Blas, Isabel | Llinares, Isabel | Alom, Jordi

Article Type: Research Article

Abstract: Some studies have determined that oxidative stress is a decisive factor in Alzheimer's disease (AD) and even suggested that it is present in the initial phase of mild cognitive impairment (MCI). The aim of our study was to investigate the process of oxidative stress by measuring the level of malondialdehyde (MDA), the specific activity of two peripheral antioxidant defenses (superoxide dismutase (SOD) and ceruloplasmin), and the level of copper in AD and MCI patients and compare those results with healthy subjects. The sample group consisted of 36 patients with AD, 18 patients with MCI, and 33 healthy aged subjects. Blood …samples were obtained from each subject. A significantly higher copper level was found in patients with AD and MCI compared to the control group. The levels of MDA showed a similar trend and were higher in patients from the AD and MCI groups than in the control group. It was found that both studied parameters had positive correlation in the whole studied population (r = 0.340; p = 0.001). A stepwise logistic regression analysis was used to identify an optimal combination of these biomarkers. The optimal biomarker combinations were MDA and SOD with area under the curve of 0.803 (0.691–0.915, CI 95%, p < 0.001) for the diagnosis of AD. The optimal cutpoint yielded 88.0% Sensitivity and 70.0% Specificity. The biomarker combinations predicted AD and were markedly superior to individual biomarkers. Our findings support the hypothesis that oxidative stress might represent a sign of AD pathology and could be an early event in the progression of MCI to AD. Show more

Keywords: Alzheimer's disease, copper, malondialdehyde, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2012-121528

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 823-829, 2013

Authors: Dubé, Joseph B. | Johansen, Christopher T. | Robinson, John F. | Lindsay, Joan | Hachinski, Vladimir | Hegele, Robert A.

Article Type: Research Article

Abstract: Dementia is a heritable condition with devastating effects on both patients and their caregivers. Studies have identified genetic variants associated with increased susceptibility to late-onset Alzheimer disease (AD)-related dementia; however, no studies have assessed whether genetic variation is associated with the early stages of cognitive decline. Given that cerebrovascular disease is an established mechanism in which chronic ischemia increases susceptibility to dementia, we assessed whether genetic variation associated with either cardio-metabolic or AD-related traits is associated with an early stage of cognitive decline called “cognitive impairment, no dementia” (CIND). We studied 484 CIND patients and 459 cognitively healthy controls selected …from the Canadian Study of Health and Aging. We tested for association between ~200,000 genetic variants selected from genes associated with cardio-metabolic traits and CIND status using the Cardio-MetaboChip. We also assessed whether AD-related variants and APOE alleles were associated with CIND status, either individually or as part of a composite genetic risk score. We identified a potential association between the ZNF608/GRAMD3 locus, specifically the rs1439568 polymorphism and CIND status (major allele odds ratio [OR] = 1.51; p = 8.4 × 10−6 ). AD-related variants were not associated with CIND status, however APOE E4 allele frequency was significantly higher in CIND patients versus healthy controls (OR = 1.35; p = 0.044). We identified a potential association between the ZNF608/GRAMD3 locus and CIND status, although AD-related variants were not associated with CIND. Additional replication of this association signal is invited. Show more

Keywords: Alzheimer's disease, APOE, cardiovascular diseases, genome-wide association study, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-2012-121477

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 831-840, 2013

Authors: Ni, Ruiqing | Marutle, Amelia | Nordberg, Agneta

Article Type: Research Article

Abstract: The nicotinic receptors (nAChRs), which play a critical role in cognitive function, are impaired early in the course of Alzheimer's disease (AD). We have previously demonstrated that amyloid-β (Aβ) assemblies bind to α7 nAChRs and form complexes in AD brain, suggesting that this cooperative process may contribute to disruption of synaptic function in AD. In the current study, we further characterized the interaction between different nAChR subtypes and fibrillar Aβ by binding assays in postmortem brain from AD and control cases using a wide range of drugs with different molecular targets, including selective nAChR subtype agonists, and the amyloid ligand …Pittsburgh compound B (PIB) that binds with high (nanomolar) affinity to fibrillar Aβ. The α7 nAChR agonists varenicline and JN403, but not the α4β2 nAChR agonist cytisine, increased the 3 H-PIB binding in autopsy tissue homogenates from AD and control frontal cortex. This effect was blocked in the presence of the α7 nAChR antagonists methyllycaconitine, α-bungarotoxin, and mecamylamine, but not by the α4β2 nAChR antagonist dihydro-β-erythroidine. Increases in 3 H-PIB binding evoked by varenicline and JN403 were also prevented by pre-incubation with another amyloid ligand, BF-227. The acetylcholinesterase inhibitor and allosteric nAChR modulator galantamine as well as the N-methyl-d-aspartate receptor blocker memantine did not significantly alter 3 H-PIB binding levels in AD brain. The present findings further support a specific interaction between fibrillar Aβ and α7 nAChRs in the brain, suggesting that treatment with α7 nAChR stimulatory drugs can modulate Aβ/α7 nAChR pathogenic signaling mechanisms in AD brain. Show more

Keywords: α7 nicotinic acetylcholine receptors, Alzheimer's disease, fibrillar amyloid-β, 3H-PIB binding, postmortem brain

DOI: 10.3233/JAD-2012-121447

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 841-851, 2013

Authors: Kim, Ggotpin | Kim, Hyesook | Kim, Ki Nam | Son, Jung In | Kim, Seong Yoon | Tamura, Tsunenobu | Chang, Namsoo

Article Type: Research Article

Abstract: Elevated homocysteine (Hcy) levels have been associated with an increased risk of cognitive impairment and Alzheimer's disease (AD). Tissue factor pathway inhibitor (TFPI) has recently emerged as a candidate marker of endothelial damage in AD. We investigated the relationship between plasma levels of folate, vitamin B12, Hcy, and TFPI, as well as cognitive function in 321 [100 each with mild cognitive impairment (MCI) and AD, 121 normal subjects] Korean elderly (mean age 74.8 ± 7.2 years). Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, Hcy by the HPLC-fluorescence method, and TFPI by enzyme-linked immunosorbent assay. Plasma Hcy levels …were higher in patients with AD and MCI than those in normal subjects (p < 0.001). The AD group had higher proportions of hyperhomocysteinemic (>15 μM) and folate deficient (<3.0 ng/mL) (p = 0.026) subjects. A multiple regression analysis after adjusting for covariates revealed positive relationships between plasma folate and the MMSE-KC and Boston Naming Test, and between plasma vitamin B12 and the Word List Memory Test in the AD group, but negative associations between plasma Hcy and the Word List Memory and Constructional Recall Tests and between plasma TFPI and the Boston Naming, Word List Recall, and Constructional Recall Tests. In contrast, only plasma folate level was positively associated with the MMSE-KC and Boston Naming Test in the MCI group. No associations were observed in the normal group. These results suggest that plasma folate, vitamin B12, Hcy, and TFPI are associated with cognitive function in cognitively impaired (AD and MCI) elderly and that the association was stronger in patients with AD. Show more

Keywords: Alzheimer's disease, cognitive function, folate, homocysteine, mild cognitive impairment, tissue factor pathway inhibitor, vitamin B12

DOI: 10.3233/JAD-2012-121345

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 853-862, 2013

Authors: Wei, Gang | Chen, Yun-bo | Chen, Dong-Feng | Lai, Xiao-Ping | Liu, Dong-Hui | Deng, Ru-Dong | Zhou, Jian-Hong | Zhang, Sai-Xia | Li, Yi-Wei | Lii, Hui | Liu, Liu-Fang | Wang, Qi | Nie, Hui

Article Type: Research Article

Abstract: β-Asarone, an active component of the Acori graminei rhizome that has been used as traditional Chinese herb, has been reported to be capable of inhibiting neuronal apoptosis. However, the signaling mechanism underlying the inhibitory effect of β-asarone has remained elusive. This study was aimed to investigate whether the CaMKII signaling pathway is involved in the β-asarone mediated neuroprotection. Using PC12 cells and primary cultures of cortical neurons treated with amyloid-β (Aβ)1-40 or Aβ1-42 peptide, we demonstrated that β-asarone can protect PC12 cells and cortical neurons and inhibit neuronal apoptosis by activating the CaMKII-α/p-CREB/Bcl-2 pathway. Moreover, CaMKII-α overexpression enhanced …the β-asarone-induced p-CREB-Bcl-2 expression and anti-apoptotic effects. Interestingly, suppression of CaMKII-α by siRNA or a specific inhibitor can significantly reduce the β-asarone-induced p-CREB and Bcl-2 expression and Aβ1-40 induced neuronal apoptosis in PC12 cells. AβPP/PS1 mice at the age of 3 months and age-matched wild-type mice were intragastrically administered β-asarone (7 mg/kg/day, 21 mg/kg/day) or a vehicle daily for 4 months. β-asarone improved cognitive function of the AβPP/PS1 mice and reduced neuronal apoptosis in the cortex of the AβPP/PS1 mice. A significant increase in CaMKII/CREB/Bcl-2 expression was observed in the cortex of the AβPP/PS1 mice treated with β-asarone. In summary, our observations demonstrated that β-asarone can inhibit neuronal apoptosis via the CaMKII/CREB/Bcl-2 signaling pathway in in vitro models and in AβPP/PS1 mice. Therefore, β-asarone can be used as a potential therapeutic agent in the long-term treatment of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, β-asarone, Bcl-2, CaMKII, neuronal apoptosis, phospho-CREB-binding protein

DOI: 10.3233/JAD-2012-120865

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 863-880, 2013

Authors: Wisniewski, Thomas | Newman, Kia | Javitt, Norman B.

Article Type: Research Article

Abstract: Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer's disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition …using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease. Show more

Keywords: Alzheimer's disease, C27 sterol intermediates, 8-dehydrocholesterol, desmosterol, DHCR24, Seladin-1

DOI: 10.3233/JAD-2012-121453

Citation: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 881-888, 2013