Journal of Alzheimer's Disease - Volume 27, issue 3

Authors: Seidl, Ulrich | Lueken, Ulrike | Thomann, Philipp A. | Geider, Josef | Schröder, Johannes

Article Type: Research Article

Abstract: Autobiographical memory comprises memories of one's own past that are characterized by a sense of subjective time and autonoetic awareness. Although autobiographical memory deficits are among the major complaints of patients with dementia, they have rarely been systematically assessed in mild cognitive impairment and Alzheimer's disease. We therefore investigated semantic and episodic aspects of autobiographical memory for remote and recent life periods in a sample of 239 nursing home residents (165 in different stages of Alzheimer's disease, 33 with mild cognitive impairment, and 41 cognitively unimpaired) with respect to potential confounders. Episodic autobiographical memories, especially the richness of details, were …impaired early in the course of Alzheimer's disease or even in the preclinical phase, while semantic memories were spared until moderate stages, indicating a dissociation between both memory systems. The examination of autobiographic memory loss can facilitate the clinical diagnosis of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, autobiographical memory, episodic memory, mild cognitive impairment, semantic memory

DOI: 10.3233/JAD-2011-110014

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 567-574, 2011

Authors: de Toledo Ferraz Alves, Tânia Corrêa | Scazufca, Márcia | Squarzoni, Paula | de Souza Duran, Fábio Luiz | Tamashiro-Duran, Jaqueline Hatsuko | Vallada, Homero P. | Andrei, Anna | Wajngarten, Mauricio | Menezes, Paulo R. | Busatto, Geraldo F.

Article Type: Research Article

Abstract: Vascular risk factors may play an important role in the pathophysiology of Alzheimer's disease (AD). While there is consistent evidence of gray matter (GM) abnormalities in earlier stages of AD, the presence of more subtle GM changes associated with vascular risk factors in the absence of clinically significant vascular events has been scarcely investigated. This study aimed to examine GM changes in elderly subjects with cardiovascular risk factors. We predicted that the presence of cardiovascular risk would be associated with GM abnormalities involving the temporal-parietal cortices and limbic structures. We recruited 248 dementia-free subjects, age range 66–75 years, from the …population-based “São Paulo Ageing and Health Study”, classified in accordance to their Framingham Coronary Heart Disease Risk (FCHDR) score to undergo an MRI scan. We performed an overall analysis of covariance, controlled to total GM and APOE4 status, to investigate the presence of regional GM abnormalities in association with FCHDR subgroups (high-risk, medium-risk, and low-risk), and followed by post hoc t-test. We also applied a co-relational design in order to investigate the presence of linear progression of the GM vulnerability in association with cardiovascular risk factor. Voxel-based morphometry showed that the presence of cardiovascular risk factors were associated with regional GM loss involving the temporal cortices bilaterally. Those results retained statistical significance after including APOE4 as a covariate of interest. We also observed that there was a negative correlation between FCHDR scores and rGM distribution in the parietal cortex. Subclinical cerebrovascular abnormalities involving GM loss may provide an important link between cardiovascular risk factors and AD. Show more

Keywords: Alzheimer's disease, elderly, MRI, population-based, vascular risk factors

DOI: 10.3233/JAD-2011-110827

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 575-589, 2011

Authors: Zimny, Anna | Szewczyk, Pawel | Trypka, Elzbieta | Wojtynska, Renata | Noga, Leszek | Leszek, Jerzy | Sasiadek, Marek

Article Type: Research Article

Abstract: The purpose of this study was to assess metabolic, perfusion, and microstructural changes within the posterior cingulate area in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) using advanced MR techniques such as: spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI). Thirty patients with AD (mean age 71.5 y, MMSE 18), 23 with aMCI (mean age 66 y, MMSE 27.4), and 15 age-matched normal controls (mean age 69 y, MMSE 29.5) underwent conventional MRI followed by MRS, PWI, and DTI on 1.5 Tesla MR unit. Several metabolite ratios (N-acetylaspartate [NAA]/creatine [Cr], choline [Ch]/Cr, myoinositol …[mI]/Cr, mI/NAA, mI/Cho) as well as parameters of cerebral blood volume relative to cerebellum and fractional anisotropy were obtained in the posterior cingulate region. The above parameters were correlated with the results of neuropsychological tests. AD patients showed significant abnormalities in all evaluated parameters while subjects with aMCI showed only perfusion and diffusion changes in the posterior cingulate area. Only PWI and DTI measurements revealed significant differences among the three evaluated subject groups. DTI, PWI, and MRS results showed significant correlations with neuropsychological tests. DTI changes correlated with both PWI and MRS abnormalities. Of neuroimaging methods, DTI revealed the highest accuracy in diagnosis of AD and aMCI (0.95, 0.79) followed by PWI (0.87, 0.67) and MRS (0.82, 0.47), respectively. In conclusion, AD is a complex pathology regarding both grey and white matter. DTI seems to be the most useful imaging modality to distinguish between AD, aMCI, and control group, followed by PWI and MRS. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, diffusion tensor imaging, magnetic resonance spectroscopy, perfusion weighted MR imaging, posterior cingulate area

DOI: 10.3233/JAD-2011-110254

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 591-601, 2011

Authors: Canu, Nadia | Filesi, Ilaria | Pristerà, Andrea | Ciotti, Maria Teresa | Biocca, Silvia

Article Type: Research Article

Abstract: The microtubule associated protein tau plays a crucial role in Alzheimer's disease and in many neurodegenerative disorders collectively known as tauopathies. Recently, tau pathology has been also documented in prion diseases although the possible molecular events linking these two proteins are still unknown. We have investigated the fate of normal cellular prion protein (PrPC ) in primary cortical neurons overexpressing tau protein. We found that overexpression of tau reduces PrPC expression at the cell surface and causes its accumulation and aggregation in the cell body but does not affect its maturation and glycosylation. Trapped PrPC forms detergent-insoluble aggregates, …mainly composed of un-glycosylated and mono-glycosylated forms of prion protein. Interestingly, co-transfection of tau gene in cortical neurons with a proteasome activity reporter, consisting of a short peptide degron fused to the carboxyl-terminus of green fluorescent protein (GFP-CL1), results in down-regulation of the proteasome system, suggesting a possible mechanism that contributes to intracellular PrPC accumulation. These findings open a new perspective for the possible crosstalk between tau and prion proteins in the pathogenesis of tau induced-neurodegeneration. Show more

Keywords: Neurodegenerative diseases, prion, proteasome activity reporter, tau, tauopathies

DOI: 10.3233/JAD-2011-110446

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 603-613, 2011

Authors: Williamson, Ritchie | van Aalten, Lidy | Mann, David M.A. | Platt, Bettina | Plattner, Florian | Bedford, Lynn | Mayer, John | Howlett, David | Usardi, Alessia | Sutherland, Calum | Cole, Adam R.

Article Type: Research Article

Abstract: Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated AβPP and PSEN1, but not AβPP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 …alone, or in cultured neurons treated with soluble, oligomeric Aβ42 peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of AβPP, but that neither excessive Aβ42 peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation. Show more

Keywords: Alzheimer's disease, Cdk5, CRMP2, GSK3, neurodegeneration, phosphorylation

DOI: 10.3233/JAD-2011-110617

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 615-625, 2011

Authors: Darby, David G. | Brodtmann, Amy | Pietrzak, Robert H. | Fredrickson, Julia | Woodward, Michael | Villemagne, Victor L. | Fredrickson, Amy | Maruff, Paul | Rowe, Christopher

Article Type: Research Article

Abstract: Intra-individual decline in memory and cognition is characteristic of prodromal Alzheimer's disease (AD) and may allow detection of very early AD pathology. Episodic memory task scores on a brief computerized cognitive battery (CogState) were prospectively evaluated at baseline, and 3-, 6-, 9-, 12-, and 24-months post-baseline. Linear mixed models were conducted to compute age-adjusted slopes. Subjects with slopes declining ≥90th percentile (“memory decliners”) and age- and gender-matched subjects without such decline (“non-decliners”) were studied with clinical, neuropsychological, and neuroimaging evaluations. Of 195 who completed 24-month evaluation (age 51 to 80 years), 15 memory decliners (mean age 62.7 years, SD 7.6) …were identified, and matched with 33 non-decliners (mean age 63.3 years, SD 8.2). Amyloid-PET imaging was qualitatively abnormal with excess cortical amyloid accumulation in 7 memory decliners (46.7%) and 4 (12.1%) non-decliners (odds ratio 6.34), and quantitatively abnormal with standardized uptake value ratios >1.4 in 5 memory decliners (33.3%) and 2 (6.1%) non-decliners (odds ratio 8.3). One of the memory decliners and none of the non-decliners fulfilled criteria for mild cognitive impairment, but the groups did not differ with respect to subjective memory impairment, neuropsychological evidence of episodic memory impairment, or MRI imaging abnormalities. Intra-individual decline in episodic memory can be detected using a brief computerized cognitive performance test optimized to detect change in community-dwelling non-demented older persons and appears predictive of the presence of cerebral amyloid in about half of these persons. This approach may help detect early prodromal AD pathology in wider-scale community screening programs. Show more

Keywords: Alzheimer's disease, cognition, cognitive decline, memory, pre-clinical diagnosis

DOI: 10.3233/JAD-2011-110818

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 627-637, 2011

Authors: Wei, Wei | Liu, Ying-Hua | Zhang, Chang-E. | Wang, Qun | Wei, Zelan | Mousseau, Darrell D. | Wang, Jian-Zhi | Tian, Qing | Liu, Gong-Ping

Article Type: Research Article

Abstract: Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen …synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits. Show more

Keywords: Aged rat, Alzheimer's disease, folate, hyperhomocysteinemia, vitamin-B12

DOI: 10.3233/JAD-2011-110770

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 639-650, 2011

Authors: Cecchi, Cristina | Evangelisti, Elisa | Cascella, Roberta | Zampagni, Mariagioia | Benvenuti, Susanna | Luciani, Paola | Deledda, Cristiana | Cellai, Ilaria | Wright, Daniel | Saccardi, Riccardo | Peri, Alessandro | Stefani, Massimo

Article Type: Research Article

Abstract: Cell therapy is a promising approach for the treatment of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. However, the presence of toxic aggregates in tissue raises the question of whether grafted stem cells are susceptible to amyloid toxicity before they differentiate into mature neurons. To address this question, we investigated the relative vulnerability of human mesenchymal stromal cells and their neuronally differentiated counterparts to Aβ42 oligomers and whether susceptibility correlates with membrane GM1 content, a key player in oligomer toxicity. We found that our cell model was highly susceptible to aggregate toxicity, whereas neuronal differentiation induced resistance to …amyloid species. This data correlated well with the content of membrane GM1, levels of which decreased considerably in differentiated cells. These findings extend our knowledge of stem cell vulnerability to amyloid species, which remains a controversial issue, and confirm that amyloid-GM1 interactions play an important role in cell impairment. Show more

Keywords: Amyloid, amyloid toxicity, calcium dysregulation, GM1, oxidative stress, stem cells

DOI: 10.3233/JAD-2011-110590

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 651-664, 2011

Authors: Bjerke, Maria | Zetterberg, Henrik | Edman, Åke | Blennow, Kaj | Wallin, Anders | Andreasson, Ulf

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are intertwined by mixed dementia (MD) harboring varying degrees of AD pathology in combination with cerebrovascular disease. The aim was to assess whether there is a difference in the cerebrospinal fluid (CSF) profile, of selected proteins, between patients with VaD and MD with subcortical vascular disease (SVD), AD, and healthy controls that could contribute in the separation of the groups. The study included 30 controls, 26 SVD patients (9 VaD and 17 MD) and 30 AD patients. The protein panel included total tau (T-tau), hyperphosphorylated tau 181 (P-tau181 ), amyloid β 1–42 (Aβ1-42 …), neurofilament light (NF-L), myelin basic protein (MBP), heart fatty acid binding protein (H-FABP), matrix metalloproteinases (MMP-1, -2, -3, -9, and -10), and tissue inhibitors of metalloproteinases (TIMP-1 and -2). Immunochemical methods were utilized for quantification of the proteins in CSF and data analysis was performed with a multivariate discriminant algorithm. The concentrations of MBP, TIMP-1, P-tau181 , NF-L, T-tau, MMP-9, Aβ1-42 , and MMP-2 contributed the most to the separation between SVD and AD, with a sensitivity of 89% and a specificity of 90% (AUC = 0.92). MBP and NF-L performed the best in discriminating SVD from controls, while T-tau and Aβ1-42 contributed the most in segregating AD from controls. The CSF biomarkers reflecting AD pathology (T-tau, P-tau181 , and Aβ1-42 ), white matter lesions (NF-L and MBP) and matrix remodeling (MMP-9 and TIMP-1) perform well in differentiating between SVD and AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, matrix metalloproteinases, myelin basic protein, neurofilament light, tau, vascular dementia

DOI: 10.3233/JAD-2011-110566

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 665-676, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110777

Citation: Journal of Alzheimer's Disease, vol. 27, no. 3, pp. 677-678, 2011