Volume 27, Number 3, December 2011

Pages 467-476
Review
Nikolai N. Sluchanko, Nikolai B. Gusev (Handling Associate Editor: Alexander Boldyrev)
Probable Participation of 14-3-3 in Tau Protein Oligomerization and Aggregation
Abstract: Aggregation of tau proteins followed by formation of paired helical filaments and neurofibrillary tangles is considered as a hallmark of certain neurodegenerative disorders such as different tauopathies and Alzheimer’s disease (AD). Tau aggregation is dependent on the presence of polyanions, cellular redox state, limited proteolysis, and different posttranslational modifications among which tau phosphorylation plays a particularly important role. Although it is still debatable whether tau aggregation is harmful or protective for the cell, detailed analysis of molecular mechanisms underlying this process seems to be of great importance for understanding AD pathogenesis. This review is focused on universal adapter proteins 14-3-3 that seem to be significant partners to tau protein in neurons. 14-3-3 interacts with nonphosphorylated tau and promotes its interaction with and phosphorylation by a number of protein kinases. 14-3-3 induces aggregation of nonphosphorylated tau and does not affect aggregation of tau phosphorylated at specific sites. Due to its high concentration in neurons, 14-3-3 can compete with tubulin for interaction with tau. Binding to phosphorylated tau, 14-3-3 might inhibit its dephosphorylation by protein phosphatases and by this means indirectly affect interaction of tau with microtubules and tau aggregation. Finally, 14-3-3 might promote sequestration of dangerous small tau oligomers and stabilize tau aggregates. We propose that 14-3-3 be considered an important participant of the complex process of tau aggregation and as a potential therapeutic target in treating AD.

Pages 477-482
Short Communication
Bechara J. Saab, Ruxandra Luca*, Wing B. Yuen*, Adam M. P. Saab, John C. Roder *These authors contributed equally to the manuscript.
Memantine Affects Cognitive Flexibility in the Morris Water Maze
Abstract: Alzheimer’s disease (AD) is multi-factorial mental disorder characterized by a copious array of congruent features cumulating in disrupted memory and dysthymia. Though the mechanism remains elusive, the highly unspecific pharmaceutical, memantine, provides modest benefits for patients with moderate-to-severe AD. A greater understanding of how memantine affects cognitive function promises to facilitate the search for better therapeutics. We therefore examined cognitive flexibility of mice following 5 and 10 mg/kg memantine administration using a platform re-location water maze. Strikingly, subjects receiving memantine demonstrated memory impairment relative to controls when re-trained off drug, revealing a novel and unusual disruption of cognitive flexibility.

Pages 483-490
Lisa Mosconi, Mony de Leon, John Murray, Lezi E, Jianghua Lu, Elizabeth Javier, Pauline McHugh, Russell H. Swerdlow (Handling Associate Editor: Paula Moreira)
Reduced Mitochondria Cytochrome Oxidase Activity in Adult Children of Mothers with Alzheimer’s Disease
Abstract: Biomarker studies demonstrate inheritance of glucose hypometabolism and increased amyloid-β deposition in adult offspring of mothers, but not fathers, affected by late-onset Alzheimer’s disease (LOAD). The underlying genetic mechanisms are unknown. We investigated whether cognitively normal (NL) individuals with a maternal history of LOAD (MH) have reduced platelet mitochondrial cytochrome oxidase activity (COX, electron transport chain complex IV) compared to those with paternal (PH) or negative family history (NH). Thirty-six consecutive NL individuals (age 55±15 y, range 27-71 y, 56% female, CDR=0, MMSE≥28, 28% APOE-4 carriers), including 12 NH, 12 PH, and 12 MH, received a blood draw to measure platelet mitochondrial COX activity. Citrate synthase activity (CS) was measured as a reference. Groups were comparable for clinical and neuropsychological measures. We found that after correcting for CS, COX activity was reduced by 29% in MH compared to NH, and by 30% in MH compared to PH (p≤0.006). Results remained significant controlling for age, gender, education, and APOE. No differences were found between PH and NH. COX measures discriminated MH from the other groups with accuracy ≥75%, and relative risk ≥3 (p≤0.005). Among NL with LOAD-parents, only those with MH showed reduced COX activity in platelet mitochondria compared to PH and NH. The association between maternal history of LOAD and systemic COX reductions suggests transmission via mitochondrial DNA, which is exclusively maternally inherited in humans.

Pages 491-498
Ana Verdelho, Sofia Madureira, Carla Moleiro, Catarina O. Santos, José M. Ferro, Timo Erkinjuntti, Anna Poggesi, Leonardo Pantoni, Franz Fazekas, Philip Scheltens, Gunhild Waldemar, Anders Wallin, Domenico Inzitari, on behalf of the LADIS Study
Self-Perceived Memory Complaints Predict Progression to Alzheimer Disease. The LADIS Study
Abstract: Memory complaints are frequent in the elderly but its implications in cognition over time remain a controversial issue. Our objective was to evaluate the risk of self perceived memory complaints in the evolution for future dementia. The LADIS (Leukoaraiosis and Disability) prospective multinational European study evaluates the impact of white matter changes (WMC) on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Dementia and subtypes of dementia were classified. Self perceived memory complaints in independent elderly were collected during the interview. MRI was performed at entry and at the end of the study. 639 subjects were included (74.1 ± 5 years old, 55% women, 9.6 ± 3.8 years of schooling). At end of follow-up, 90 patients were demented (vascular dementia, 54; Alzheimer’s disease (AD) and AD with vascular component, 34; frontotemporal dementia, 2). Using Cox regression analysis, we found that self perceived memory complaints were a strong predictor of AD and AD with vascular component during the follow-up (β= 2.7, p=0.008; HR=15.5, CI 95% [2.04,117.6]), independently of other confounders, namely depressive symptoms, WMC severity, medial temporal lobe atrophy, and global cognition status at baseline. Self perceived memory complaints did not predict vascular dementia. In the LADIS study, self perceived memory complaints predicted AD but not vascular dementia in elderly subjects with WMC living independently.

Pages 499-510
Jukka Puoliväli, Antti Nurmi, Taina-Kaisa Miettinen, Antonio Soleti, Francesca Riccardino, Giedrius Kalesnykas, Taneli Heikkinen, Nina Vartiainen, Raimo Pussinen, Leena Tähtivaara, Kimmo Lehtimäki, Juha Yrjänheikki, Donatella Canistro, Andrea Sapone, Enzo Spisni, Moreno Paolini (Handling Associate Editor: Federico Licastro)
The Radical Scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) Decreases Mortality, Enhances Cognitive Functions in Water Maze and Reduces Amyloid Plaque Burden in hAβPP Transgenic Mice
Abstract: The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-β (Aβ) accumulation in an Alzheimer’s disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aβ plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons.

Supplementary Data for Puoliväli et al. article (PDF)

Pages 511-520
Charlotte Bauer*, Raphaëlle Pardossi-Piquard*, Julie Dunys, Maggie Roy, Frédéric Checler (Handling Associate Editor: Othman Ghribi) *Equal contribution to this work
γ-Secretase-Mediated Regulation of Neprilysin: Influence of Cell Density and Aging and Modulation by Imatinib
Abstract: Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer’s disease (AD)-associated amyloid-β peptides (Aβ) in the brain. The ectopeptidase, neprilysin (NEP), has been reported as the major Aβ-degrading enzyme in mice and human brains. We have previously shown that NEP expression and activity are regulated by AICD, the intracellular domain of the amyloid-β protein precursor (AβPP) generated by γ-secretase. Thus, NEP transcription, expression, and enzymatic activity are dramatically reduced in fibroblasts devoid of AβPP (the precursor of AICD) or lacking both presenilin (PS) 1 and 2 (two parent proteins contributing to AICD formation). We demonstrate here that NEP expression and activity are influenced by a number of cell passages and density, and we confirm a drastic reduction of NEP expression and activity in AβPP and PS null fibroblasts examined at similar passages and cell densities. Furthermore, Imatinib (Gleevec), a known tyrosine kinase inhibitor was recently shown to elevate AICD in H4 human neuroglioma cells, and this was accompanied by concomitant increases of NEP protein, mRNA levels, and activity. However, the demonstration of a causal link between Imatinib and AICD levels was still lacking. We show here an Imatinib-dependent effect on NEP expression and activity in murine fibroblasts and establish that Imatinib-induced modulation of NEP was abolished by the depletion of AβPP or its homologues APLP1 and APLP2, thereby confirming that Imatinib-mediated control of NEP could indeed be accounted for its effect on AICD.

Pages 521-530
Shane Kavanagh, Bart Van Baelen, Barbara Schäuble
Long-term Effects of Galantamine on Cognitive Function in Alzheimer’s Disease: A Large-Scale International Retrospective Study
Abstract: In Alzheimer’s disease (AD), it is important to consider long-term effects, not only in patients receiving treatment, but also in subjects in whom therapy has been discontinued. The present analysis evaluates the long-term effects of galantamine on cognitive function in AD in terms of Mini-Mental State Examination (MMSE) scores for up to 7 years, using both clinical data and epidemiological modeling. Consideration is given not only to patients continuing to receive galantamine therapy, but also to those who stop this treatment. In a retrospective review of medical notes, re-contacted study investigators obtained data from 258 patients originally recruited into three previously described randomized clinical trials involving galantamine: two placebo-controlled trials in mild-to-moderate AD (of 3 and 6 months’ duration, followed by open-label extensions) and the galantamine-treatment arm of a 12-month comparative study with donepezil in moderate AD. Information relating to disease progression was collated (up to five MMSE scores, separated by at least 3 months, for each patient). Changes in MMSE scores over time were evaluated using observed data. In the absence of long-term placebo, the rate of cognitive decline without treatment was projected using a previously described epidemiological model. A new, exploratory statistical model was also developed. Results showed that patients with mild-to-moderate AD who received long-term galantamine treatment exhibited attenuated decline in cognitive function, as assessed by MMSE, compared with decline predicted in the absence of treatment. Furthermore, patients who stopped treatment experienced subsequent cognitive decline at a rate similar to that predicted for untreated patients.

Supplementary Data for Kavanagh et al. article (PDF)

Pages 531-541
Sadayuki Hashioka, James G. McLarnon, Jae K. Ryu, Amal M. Youssef, Alaa S. Abd-El-Aziz, Edward G. Neeland, Andis Klegeris (Handling Associate Editor: João B. Calixto)
Pyrazole compound 2-MBAPA as a novel inhibitor of microglial activation and neurotoxicity in vitro and in vivo
Abstract: Pyrazole derivatives are well documented to possess anti-inflammatory activity but their effects on microglial activation are unknown. We determined the efficacy of the novel pyrazole compound 2-MBAPA (R/S-(±)-2-Methylbenzylamino 2-oxo-N-[4-cyano-1-phenyl-1H-pyrazol-5-yl] acetamide) on activated microglia under conditions relevant to inflammation in Alzheimer’s disease (AD) brain. The compound at a non-toxic concentration inhibited secretion of tumor necrosis factor (TNF)-α by activated human microglia and attenuated toxicity of conditioned medium from activated human microglia towards human SH-SY5Y neuroblastoma cells in vitro. The 2-MBAPA neuroprotection was further demonstrated in vivo using an animal model of AD. The compound inhibited microgliosis, but not astrogliosis, in amyloid-β peptide (Aβ)1-42-injected rat brain. 2-MBAPA also diminished neuronal loss in the dentate gyrus caused by Aβ1-42 injection. These results indicate that this novel pyrazole compound confers neuroprotection by inhibiting microglial activation. Therefore, further studies with 2-MBAPA and novel analogues based on this lead compound are warranted in an effort to develop new pharmacological agents that may be useful for slowing down progression of AD and other neuroinflammatory disorders associated with activated microglia.

Pages 543-551
William G. Britt III, Anne M. Hansen, Sofia Bhaskerrao, James P. Larsen, Floyd Petersen, April Dickson, Cindy Dickson, Wolff M. Kirsch
Mild Cognitive Impairment: Prodromal Alzheimer’s Disease or Something Else?
Abstract: The majority of mild cognitive impairment (MCI) studies use baseline and one follow-up measurement to determine the clinical course of the disorder. This report of MCI clinical course is based on the a statistical evaluation of multiple neurocognitive tests over a 60 month period in elderly normal and MCI cohorts. The data includes serial informant-based measures (Clinical Dementia Rating [CDR]) and a comprehensive battery of neuropsychological tests analyzed by two different regression methods. Twenty-nine elderly participants entered the study as neurocognitively normal; 26 remained normal, 2 progressed to MCI, and 1 progressed to dementia. Eighty-three participants entered the study as multiple domain MCI cases; 10 became normal, 46 remained MCI, and 27 progressed to dementia. Three of the 27 demented died with full necropsies performed (one case was progressive supranuclear palsy and two confirmed Alzheimer’s disease with severe cerebral amyloid angiopathy (CAA)). Without serial measures, 1 in 8 MCI could be misclassified as “stable MCI” despite reverting to normal. The stable MCI cohorts did not benefit from practice effects though the normal subjects did. Applying Classification and Regression Tree (CART) analysis enabled prediction of the endpoint status of participants from baseline values with 78.6% accuracy. The fluctuating cognitive status of the multiple domain MCI cases implies a remitting pathologic process with elements of recovery consistent with a progressive microvasculopathy such as CAA.

Pages 553-566
Lenore Arab, Mary L Biggs, Ellen S O’Meara, WT Longstreth, Jr, Paul K Crane, Annette L Fitzpatrick
Gender Differences in Tea, Coffee, and Cognitive Decline in the Elderly: The Cardiovascular Health Study
Abstract: Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

Pages 567-574
Ulrich Seidl, Ulrike Lueken, Philipp A. Thomann, Josef Geider, Johannes Schröder
Autobiographical Memory Deficits in Alzheimer’s Disease
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.

Pages 575-589
Tânia Corrêa de Toledo Ferraz Alves, Márcia Scazufca, Paula Squarzoni, Fábio Luiz de Souza Duran, Jaqueline Hatsuko Tamashiro-Duran, Homero P. Vallada, Anna Andrei, Mauricio Wajngarten, Paulo R. Menezes, Geraldo F. Busatto (Handling Associate Editor: Jack de la Torre)
Subtle Gray Matter Changes in Temporo-Parietal Cortex Associated with Cardiovascular Risk Factors
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.

Pages 591-601
Anna Zimny, Pawel Szewczyk, Elzbieta Trypka, Renata Wojtynska, Leszek Noga, Jerzy Leszek, Marek Sasiadek (Handling Associate Editor: Fereshteh Sedaghat)
Multimodal Imaging in Diagnosis of Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: Value of Magnetic Resonance Spectroscopy, Perfusion, and Diffusion Tensor Imaging of the Posterior Cingulate Region
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.

Pages 603-613
Nadia Canu, Ilaria Filesi, Andrea Pristerà, Maria Teresa Ciotti, Silvia Biocca (Handling Associate Editor: Massimo Tabaton)
Altered Intracellular Distribution of PrPC and Impairment of Proteasome Activity in Tau Overexpressing Cortical Neurons
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.

Pages 615-625
Ritchie Williamson, Lidy van Aalten, David M.A. Mann, Bettina Platt, Florian Plattner, Lynn Bedford, John Mayer, David Howlett, Alessia Usardi, Calum Sutherland, Adam R. Cole
CRMP2 Hyperphosphorylation is Characteristic of Alzheimer’s Disease and Not a Feature Common to Other Neurodegenerative Diseases
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.

Supplementary Data for Williamson et al. article (PDF)

Pages 627-637
David G Darby, Amy Brodtmann, Robert H Pietrzak, Julia Fredrickson, Michael Woodward, Victor L Villemagne, Amy Fredrickson, Paul Maruff, Christopher Rowe
Episodic Memory Decline Predicts Cortical Amyloid Status in Community-Dwelling Older Adults
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.

Pages 639-650
Wei Wei*, Ying-Hua Liu*, Chang-E Zhang*, Qun Wang, Zelan Wei, Darrell D. Mousseau, Jian-Zhi Wang, Qing Tian, Gong-Ping Liu *Equally contributed to the paper.
Folate/vit-B12 Prevents Chronic Hyperhomocysteinemia-Induced Tau Hyperphosphorylation and Memory Deficits in Aged Rats
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.

Pages 651-664
Cristina Cecchi*, Elisa Evangelisti*, Roberta Cascella, Mariagioia Zampagni, Susanna Benvenuti, Paola Luciani, Cristiana Deledda, Ilaria Cellai, Daniel Wright, Riccardo Saccardi, Alessandro Peri, Massimo Stefani *These authors contributed equally to this work.
Neuronal Differentiation of Human Mesenchymal Stromal Cells Increases Their Resistance to Aβ42 Aggregate Toxicity
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.

Pages 665-676
Maria Bjerke, Henrik Zetterberg, Åke Edman, Kaj Blennow, Anders Wallin, Ulf Andreasson
Cerebrospinal Fluid Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Combination with Subcortical and Cortical Biomarkers in Vascular Dementia and Alzheimer’s Disease
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.

RETURN TO INDEX