Journal of Alzheimer's Disease - Volume 27, issue 4

Authors: Chen, Ming | Nguyen, Huey T. | Sawmiller, Darrell R.

Article Type: Research Article

Abstract: We have contended that senile conditions—illnesses after age 60 and fully age-penetrating, such as tooth, hearing or memory loss—are not distinct “diseases” in medical nature, because they are caused by aging. Since the pace of aging varies among individuals and is much influenced by risk factors, senile conditions will only affect some but not all elderly. However, perhaps due to its unusually heavy burdens and tremendous social pressures, senile dementia (SD) has been singled out from other senile conditions and redefined as a curable “disease” (Alzheimer's). This highly popular definition has thus opened a Pandora's box that has been confusing …us up until now and warrants further scrutiny. In this article we discuss: a) what should we logically look for in SD beyond “pathogenic” factors?; b) why Ca2+ , a central regulator in neurotransmission, should be the primary player in SD; c) why the functionality of Ca2+ signaling, or its vibrant wave frequency and amplitude, must undergo down-regulation during aging, though this is intriguingly accompanied by an increase of Ca2+ “levels”; d) why intervention for SD should target Ca2+ function by promoting energy metabolisms and by Ca2+ agonists such as caffeine and nicotine, but not by “antagonists” as widely believed; and e) why our study should focus on aging, not “cell death”, a seemingly attractive paradigm but perhaps too late for intervention. We also seek answers for why unproven hypotheses can become dogmas and inhibit self-correcting mechanisms of science. Show more

Keywords: Alzheimer's disease, amyloid, calcium, review

DOI: 10.3233/JAD-2011-111142

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 679-689, 2011

Authors: Clark, Ian A. | Atwood, Craig S.

Article Type: Research Article

Abstract: This commentary addresses a novel mechanism by which aging-related changes in reproductive hormones could mediate their action in the brain. It presents the evidence that dyotic endocrine signals modulate the expression of tumor necrosis factor (TNF) and related cytokines, and that these cytokines are a functionally important downstream link mediating neurodegeneration and dysfunction. This convergence of dyotic signaling on TNF-mediated degeneration and dysfunction has important implications for understanding the pathophysiology of AD, stroke, and traumatic brain disease, and also for the treatment of these diseases.

Keywords: Alzheimer's disease, anxiety, cell cycle, dyotic signaling, endocrine dyscrasia, etanercept, inflammation, oxytocin, sex hormones, tumor necrosis factor (TNF)

DOI: 10.3233/JAD-2011-110887

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 691-699, 2011

Authors: Lloret, Ana | Badia, Mari-Carmen | Giraldo, Esther | Ermak, Gennady | Alonso, Maria-Dolores | Pallardó, Federico V. | Davies, Kelvin J.A. | Viña, Jose

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ) toxicity and tau hyperphosphorylation are hallmarks of Alzheimer's disease (AD). How their molecular relationships may affect the etiology, progression, and severity of the disease, however, has not been elucidated. We now report that incubation of fetal rat cortical neurons with Aβ upregulates expression of the Regulator of Calcineurin gene RCAN1, and this is mediated by Aβ-induced oxidative stress. Calcineurin (PPP3CA) is a serine-threonine phosphatase that dephosphorylates tau. RCAN1 proteins inhibit this phosphatase activity of calcineurin. Increased expression of RCAN1 also causes upregulation of glycogen synthase kinase-3β (GSK3β), a tau kinase. Thus, increased RCAN1 expression might be expected …to decrease phospho-tau dephosphorylation (via calcineurin inhibition) and increase tau phosphorylation (via increased GSK3β activity). Indeed, we find that incubation of primary cortical neurons with Aβ results in increased phosphorylation of tau, unless RCAN1 gene expression is silenced, or antioxidants are added. Thus we propose a mechanism to link Aβ toxicity and tau hyperphosphorylation in AD: In our hypothesis, Aβ causes mitochondrial oxidative stress and increases production of reactive oxygen species, which result in an upregulation of RCAN1 gene expression. RCAN1 proteins then both inhibit calcineurin and induce expression of GSK3β. Both mechanisms shift tau to a hyperphosphorylated state. We also find that lymphocytes from persons whose ApoE genotype is ε4/ε4 (with high risk of developing AD) show higher levels of RCAN1 and phospho-tau than those carrying the ApoE ε3/ε3 or ε3/ε4 genotypes. Thus upregulation of RCAN1 may be a valuable biomarker for AD risk. Show more

Keywords: Alzheimer's disease, amyloid-β toxicity, oxidative stress, RCAN1

DOI: 10.3233/JAD-2011-110890

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 701-709, 2011

Authors: Yang, Jing | Lunde, Lisa K. | Nuntagij, Paworn | Oguchi, Tomohiro | Camassa, Laura M.A. | Nilsson, Lars N.G. | Lannfelt, Lars | Xu, Yuming | Amiry-Moghaddam, Mahmood | Ottersen, Ole Petter | Torp, Reidun

Article Type: Research Article

Abstract: Aquaporin-4 (AQP4) is the predominant water channel in brain and is selectively expressed in astrocytes. Astrocytic endfoot membranes exhibit tenfold higher densities of AQP4 than non-endfoot membranes, making AQP4 an excellent marker of astrocyte polarization. Loss of astrocyte polarization is known to compromise astrocytic function and to be associated with impaired water and K+ homeostasis. Here we investigate by a combination of light and electron microscopic immunocytochemistry whether amyloid deposition is associated with a loss of astrocyte polarization, using AQP4 as a marker. We used the tg-ArcSwe mouse model of Alzheimer's disease, as this model displays perivascular plaques as …well as plaques confined to the neuropil. 3D reconstructions were done to establish the spatial relation between plaques and astrocytic endfeet, the latter known to contain the perivascular pool of AQP4. Changes in AQP4 expression emerge just after the appearance of the first plaques. Typically, there is a loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits, combined with an upregulation of AQP4 in the neuropil surrounding plaques. By electron microscopy it could be verified that the upregulation reflects an increased concentration of AQP4 in those delicate astrocytic processes that abound in synaptic regions. Thus, astrocytes exhibit a redistribution of AQP4 from endfoot membranes to non-endfoot membrane domains. The present data suggest that the development of amyloid deposits is associated with a loss of astrocyte polarization. The possible perturbation of water and K+ homeostasis could contribute to cognitive decline and seizure propensity in patients with Alzheimer's disease. Show more

Keywords: Aquaporin-4, cerebral amyloid angiopathy, electron microscopy, immunocytochemistry, 3D reconstruction

DOI: 10.3233/JAD-2011-110725

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 711-722, 2011

Authors: Reese, Jens Peter | Heßmann, Philipp | Seeberg, Greta | Henkel, Dajana | Hirzmann, Pamela | Rieke, Jürgen | Baum, Erika | Dannhoff, Frank | Müller, Matthias J. | Jessen, Frank | Geldsetzer, Monika-Balzer | Dodel, Richard

Article Type: Research Article

Abstract: The study aims to report service use and costs for patients with Alzheimer's disease (AD) and to explore the incremental influence of sociodemographic and illness-related determinants in ambulatory and inpatient settings within the German health care system. 395 patients with dementia were recruited at the following sites: 1) University hospital, 2) general practitioners' offices, 3) office-based neurologists, 4) a regional psychiatric hospital, and 5) nursing homes. Sociodemographic, economic, and clinical parameters were assessed using a standardized questionnaire. Informal care was not evaluated. Disease severity was measured using the Mini-Mental Status Examination and the Alzheimer's Disease Assessment Scale - Cognitive Subscale. …Neuropsychiatric status was assessed using the Geriatric Depression Scale, the Neuropsychiatric Inventory, and the Alzheimer's Disease Cooperative-Study-Activities of Daily Living. Annual total costs were estimated to be $\euro$13,080 per patient. The most important cost component was (long-term) care, constituting about 43% of total costs. Indirect costs comprised about 18% of total costs and were mainly due to reductions in working time of caregivers. Poorer functional status was associated with higher total and caregiving costs. In multivariate analyses, we identified younger age, female gender, and impaired activities of daily living as independent predictors of higher costs. Given that care for patients with AD is complex and expensive, our models were only able to explain about 17–43% of the variability in total costs. This suggests that further social and individual factors considerably influence the costs associated with AD. Direct medical care costs and long-term care costs related differently to the patient's clinical characteristics. Longitudinal and population-based studies are necessary for thoroughly evaluating the burden of disease. Show more

Keywords: Cost, dementia, economic burden, long-term care

DOI: 10.3233/JAD-2011-110539

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 723-736, 2011

Authors: Picco, Agnese | Archetti, Silvana | Ferrara, Michela | Arnaldi, Dario | Piccini, Alessandra | Serrati, Carlo | di Lorenzo, Diego | Morbelli, Silvia | Nobili, Flavio

Article Type: Research Article

Abstract: This study describes late-onset Alzheimer's disease (LOAD) in the mild cognitive impairment (MCI) stage, debuting with seizures in a 72 year-old woman. Prodromal AD was consistently diagnosed with four among amyloidosis and neurodegeneration biomarkers about 1 year after onset of seizures. Genetic assessment demonstrated apolipoprotein E ε2/ε3 genotype and three intronic single nucleotide substitutions, two in presenilin 1 and one in amyloid-β protein precursor genes. This case of seizures at onset of LOAD with severe signs of brain amyloidosis and neurodegeneration but with just MCI leads to a re-appraisal of the intriguing relationship between AD pathology and neuron excitability in …humans. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biological markers, presenilins, seizures

DOI: 10.3233/JAD-2011-110896

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 737-742, 2011

Authors: Rockenstein, Edward | Ubhi, Kiren | Doppler, Edith | Novak, Philipp | Moessler, Herbert | Li, Bin | Blanchard, Julie | Grundke-Iqbal, Inge | Iqbal, Khalid | Mante, Michael | Adame, Anthony | Crews, Leslie | Masliah, Eliezer

Article Type: Research Article

Abstract: Adult neurogenesis, the production of new neurons in certain brain regions, is known to decrease with age and the loss of neurogenic potential has been implicated in Alzheimer's disease (AD), a leading cause of dementia in the elderly. Cerebrolysin (CBL) has been shown to increase neurogenesis in models of stroke and AD. CBL is composed of small peptides with activity similar to neurotrophic factors including ciliary neurotrophic factor (CNTF), which may mediate its neurogenic effects. This study compares the effects of CBL and two peptides with corresponding to an active region of CNTF (Peptide 6 and 6A) across neurogenic brain …regions in amyloid-β protein precursor (AβPP) transgenic (tg) mice. Both CBL and Peptides 6 and 6A were able to increase the numbers of neuroblasts (DCX+ cells) and BrdU+ cells in a regionally specific manner across the subventricular zone, olfactory bulb, and hippocampus. The increased generation of new cells and cell survival in animals treated with Peptides 6 and 6A was accompanied by an increase in PCNA+ cells. In contrast, AβPP tg mice treated with CBL displayed reduced levels of TUNEL staining, while levels of PCNA were unaltered. Collectively these results demonstrate that while CBL and Peptides 6 and 6A all potentiate neurogenesis in the AβPP tg mice, their relative modes of action may differ with CBL associated with reduced apoptosis and Peptides 6 and 6A working by augmenting cell proliferation. These results are consistent with a potential therapeutic relevance for Peptides 6 and 6A in AD and other disorders characterized by neurogenic deficits. Show more

Keywords: Alzheimer's disease, neurogenesis, transgenic

DOI: 10.3233/JAD-2011-110914

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 743-752, 2011

Authors: Sinha, Maitrayee | Behera, Prajna | Bhowmick, Pritha | Banerjee, Kalpita | Basu, Sumitran | Chakrabarti, Sasanka

Article Type: Research Article

Abstract: The entangled relationship of brain aging, mitochondrial dysfunction, and amyloid-β peptide (Aβ42 ) toxicity occupies the center stage in the pathogenesis of Alzheimer's disease (AD). The present study examines some of the toxic effects of Aβ42 on brain mitochondria and provides evidence that aged brain mitochondria are significantly more vulnerable to Aβ42 toxicity. In particular, the study has shown that the aggregated, but not the monomeric, form of Aβ42 in varying concentrations (10–40 μM) during in vitro incubation causes a loss of mitochondrial membrane potential, a decrease in phosphorylation capacity and ATP synthesis, and the release of …cytochrome c from the mitochondria but without any noticeable change in the activities of respiratory chain complexes. Such effects of Aβ42 are strikingly more conspicuous on aged rat (22–24 months) brain mitochondria compared to that on brain mitochondria of young rats (4–6 months). More interestingly is the observation that in contrast to young rat brain mitochondria, a significantly higher level of Aβ42 remains associated with aged brain mitochondria under basal incubation condition as well as after exposure to exogenously added peptide. Extrapolated to an in vivo scenario, the results have clear implications in AD pathogenesis and also partly explain why brain aging is a dominant risk factor for this disease condition. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, brain aging, cytochrome c, mitochondria, respiratory chain complexes

DOI: 10.3233/JAD-2011-110686

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 753-765, 2011

Authors: Gauci, Alison J. | Caruana, Mario | Giese, Armin | Scerri, Charles | Vassallo, Neville

Article Type: Research Article

Abstract: Amyloid-β (Aβ) aggregation is a recognized key process in the pathogenesis of Alzheimer's disease (AD). Misfolded Aβ peptides self-assemble into higher-order oligomers that compromise membrane integrity, leading to synaptic degeneration and neuronal cell death. The main aim of this study was to explore whether small-molecule compounds and black tea extract can protect phospholipid membranes from disruption by Aβ aggregates. We first established a robust protocol for aggregating Aβ42 peptides into a range of oligomers that efficiently permeabilized small unilamellar liposomes. Next, 15 natural plant polyphenolic compounds, 8 N′-benzylidene-benzohydrazide (NBB) compounds and black tea extract were assessed for their ability …to antagonize liposome permeabilization by the Aβ42 oligomers. Our data indicates that black tea extract, the flavones apigenin and baicalein, and the stilbene nordihydroguaiaretic acid (NDGA) are indeed potent inhibitors. Taking into consideration the results of all the small-molecule polyphenols and NBB compounds, it can be proposed that a dihydroxyphenyl ring structure, alone or as part of a flavone scaffold, is particularly effective for protection against membrane damage by the Aβ42 oligomers. Given the critical role of membrane perforation in the neurodegenerative cascade, these conclusions may guide the design and development of novel therapeutic drugs in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, black tea, liposomes, N′-benzylidene-benzohydrazide, oligomers, polyphenols

DOI: 10.3233/JAD-2011-111061

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 767-779, 2011

Authors: Carecchio, Miryam | Fenoglio, Chiara | Cortini, Francesca | Comi, Cristoforo | Benussi, Luisa | Ghidoni, Roberta | Borroni, Barbara | De Riz, Milena | Serpente, Maria | Cantoni, Claudia | Franceschi, Massimo | Albertini, Valentina | Monaco, Francesco | Rainero, Innocenzo | Binetti, Giuliano | Padovani, Alessandro | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers (Aβ1-42 , total tau, P-181 tau) are currently used to support a clinical diagnosis of Alzheimer's disease (AD). The CSF profile in frontotemporal lobar degeneration (FTLD) caused by Progranulin (GRN) mutation is unknown. We assessed CSF biomarkers in 145 AD, 140 FTLD (20 GRN positive, 120 GRN negative) patients, and 38 controls. Taking into account the reference values used in clinical practice, GRN mutation carriers and controls did not differ significantly for any biomarker, whereas GRN negative FTLD patients had higher tau levels than controls (p < 0.001) and patients carrying GRN Thr272fs mutation (p = …0.033, Chi-Square test). Comparing CSF biomarkers mean values among groups, total tau was significantly increased in GRN negative FTLD and in mutation carriers compared with controls (p < 0.001). P-181 tau CSF was increased in AD patients and in GRN negative FTLD compared with controls (p < 0.001), but not in 17 patients carrying the Thr272fs mutation. 88.2% of mutation carriers had normal CSF tau, despite the neurodegenerative nature of FTLD. Our results suggest that GRN mutation carriers have normal or borderline CSF biomarkers. In patients with an AD-like phenotype but normal or borderline CSF biomarkers, a diagnosis of FTLD-U caused by GRN mutations should be considered. Show more

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal lobar degeneration (FTLD), neurodegeneration, progranulin, tau

DOI: 10.3233/JAD-2011-111046

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 781-790, 2011

Authors: Cerami, Chiara | Marcone, Alessandra | Galimberti, Daniela | Villa, Chiara | Scarpini, Elio | Cappa, Stefano F.

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a common early-onset dementia, which shows highly heterogeneous phenotypic presentations. Although an autosomal dominant transmission can be found only in about 10% cases, familial aggregation is frequently observed in FTLD. Recently, the progranulin gene (GRN) was reported to be involved in the disease pathogenesis. We describe two clinically different, apparently sporadic FTLD cases, sharing the previously described GRN mutation g.11019_11022delCACT (relative to nt1, NCBI NG_007886.1), alias Thr272fs, with a premorbid psychiatric history. Both patients are males and were in their sixties when diagnosed clinically with, respectively, the behavioral variant of frontotemporal dementia (bvFTD) and progressive …nonfluent aphasia (PNFA). In both cases, the medical history revealed the presence of bipolar spectrum disorders. Mutations in GRN are considered to be a major cause of FTLD. However, the phenotypes associated with these mutations are highly variable. Our description of two novel FTLD genetic cases confirms the high frequency of the g.11019_11022delCACT mutation in Northern Italy. On this basis, we recommend to consider the presence of this mutation as a possible cause of the disease, particularly in patients with premorbid psychiatric symptoms. Show more

Keywords: Bipolar disorder, dementia, frontotemporal dementia, frontotemporal lobar degeneration, GRN mutation, primary progressive nonfluent aphasia

DOI: 10.3233/JAD-2011-110788

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 791-797, 2011

Authors: Guan, Jun-Wen | Huang, Chang-Quan | Li, Yong-Hong | Wan, Chao-Min | You, Chao | Wang, Zheng-Rong | Liu, Yan-You | Liu, Qing-Xiu

Article Type: Research Article

Abstract: This study examined the association between hypertension and AD by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to February 2011. All studies that examined the association of hypertension or antihypertensive medication use with the onset of AD were included. Pooled relative risks (RR) were calculated using fixed and random effects models. Twelve studies met our inclusion criteria for this meta-analysis. All subjects were without dementia at baseline. Among them, 9 studies compared the incidence of AD between subjects with (7,270) and without (8,022) hypertension. The quantitative meta-analysis showed that there was …no significant difference in incidence of AD (RR: 1.02, 95% confidence interval (CI): 0.91–1.14) between subjects with and without hypertension. Seven studies compared the incidence of AD between subjects with (8,703) and without (13,041) antihypertensive medication use. The quantitative meta-analysis showed that there was no significant difference in incidence of AD (RR: 0.90, 95% CI: 0.79–1.03) between subjects with and without antihypertensive medication use. The quantitative meta-analysis showed that neither hypertension nor antihypertensive medication use was associated with risk for incident AD. Show more

Keywords: Alzheimer's disease, hypertension, meta-analysis

DOI: 10.3233/JAD-2011-111160

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 799-807, 2011

Authors: Licastro, Federico | Carbone, Ilaria | Ianni, Manuela | Porcellini, Elisa

Article Type: Research Article

Abstract: Genome wide association investigations from large cohorts of patients with Alzheimer's disease (AD) and non demented controls (CTR) showed that a limited set of genes were associated (p > 10−5 ) with the disease. A very recent study from our group showed that an additional limited group of SNP in selected genes were associated with AD. In this report we argue that the association of these genes with AD is suggestive of a pivotal role of environmental factors in the pathogenesis of the disease and one of these factors is virus infection. In other words, the genetic signature revealed by …genome wide association (GWA) studies discloses a network of genes that might influence the ability of the central nervous system to cope with and fight against the invasion by virus of the herpes family. In fact, Nectin-2 (NC-2); apolipoprotein E (APOE); glycoprotein carcinoembryonic antigen related cell adhesion molecule-16 (CEACAM-16); B-cell lymphoma-3 (Bcl-3); translocase of outer mitochondrial membrane 40 homolog (T0MM-40); complement receptor-1 (CR-l); APOJ or clusterin and C-type lectin domain A family-16 member (CLEC-16A); Phosphatidyl inositol- binding clathrin assembly protein gene (PICALM); ATP-bonding cassette, sub family A, member 7 (ABCA7); membrane spanning A4 (MSA4); CD2 associated protein (CD2AP); cluster of differentiation 33 (CD33); and ephrin receptor A1 (EPHA1) result in a genetic signature that might affect individual brain susceptibility to infection by the herpes virus family during aging, leading to neuronal loss, inflammation, and amyloid deposition. Show more

Keywords: Alzheimer's disease, genetic background, GWA studies, herpes-virus

DOI: 10.3233/JAD-2011-110755

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 809-817, 2011

Authors: Bihaqi, Syed Waseem | Huang, Hui | Wu, Jinfang | Zawia, Nasser H.

Article Type: Research Article

Abstract: The beginnings of late onset Alzheimer's disease (LOAD) are still unknown; however, the progressive and latent nature of neurodegeneration suggests that the triggering event occurs earlier in life. Aging primates exposed to lead (Pb) as infants exhibited an overexpression of the amyloid-β protein precursor (AβPP), amyloid-β (Aβ) and enhanced pathologic neurodegeneration. In this study, we measured the latent expression of a wide array of brain-specific genes and explored whether epigenetic pathways mediated such latent molecular and pathological changes. We analyzed the levels of proteins associated with DNA methylation, i.e., DNA methyltransferase 1 (Dnmt1), DNA methyltransferase3a (Dnmt3a), methyl-CpG binding protein-2 (MeCP2) …and those involved in histone modifications (acetylated and methylated histones). We monitored the expression profiles of these intermediates across the lifespan and analyzed their levels in 23-year-old primate brains exposed to Pb as infants. Developmental Pb exposure altered the gene expression of the arrayed genes, which were predominately repressed, with fewer upregulated genes. The latent induction and repression of genes was accompanied by a significant decrease in the protein levels of Dnmts, MeCP2, and proteins involved in histone modifications. The attenuation of DNA methylation enzymes is consistent with hypomethylating effects, which promote upregulation of the genes, while the alterations in the histone modifiers are associated with the repression of genes. Hence, we deduce that early life exposure to Pb can reprogram gene expression resulting in both upregulation and down-regulation of genes through alternate epigenetic pathways contributing to an enhancement in neurodegeneration in old age. Show more

Keywords: aging, Alzheimer's disease, DNA methylation, gene expression, histone modifications, Pb

DOI: 10.3233/JAD-2011-111013

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 819-833, 2011

Authors: Taghavi, Ali | Nasir, Samir | Pickhardt, Marcus | Hauβen, Roland Heyny-von | Mall, Gerhard | Mandelkow, Eckhard | Mandelkow, Eva-Maria | Schmidt, Boris

Article Type: Research Article

Abstract: The structure activity relationship of N′-benzylidene-benzohydrazide (NBB) binding to tau and paired helical filament (PHF) proteins as well as amyloid-β1-42 fibrils indicate differential selectivity for these protein aggregates. The ability of the compounds to stain neurofibrillary tangles and senile plaques isolated from human AD brain was investigated histochemically. These studies resulted in several tau-PHF and amyloid-β1-42 fibril selective ligands respectively. Supported by these results, we rationalized a model for the design of selective ligands for tau, PHF, and amyloid-β1-42 fibrils.

Keywords: Alzheimer's disease, amyloid-β, amphiphilicity, amphiphilic ligands, N′-benzylidene-benzohydrazide, neurofibrillary tangle, paired helical filament, selective tau ligands, tau, tau and PHF proteins

DOI: 10.3233/JAD-2011-111238

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 835-843, 2011

Authors: Dumurgier, Julien | Paquet, Claire | Peoc'h, Katell | Lapalus, Pauline | Mouton-Liger, François | Benisty, Sarah | Chasseigneaux, Stéphanie | Chabriat, Hughes | Hugon, Jacques

Article Type: Research Article

Abstract: Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ1-42 ), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aβ1-42 level was inversely associated with CSF to plasma glucose ratio (Spearman's coefficient = −0.27, p = 0.008). …This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (β [SE] of linear regression = −0.93 [0.37], p = 0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, biomarkers, CSF, glucose

DOI: 10.3233/JAD-2011-111007

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 845-851, 2011

Authors: Lebbadi, Meryem | Julien, Carl | Phivilay, Alix | Tremblay, Cyntia | Emond, Vincent | Kang, Jing X. | Calon, Frédéric

Article Type: Research Article

Abstract: Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) reduces amyloid-β (Aβ) and tau pathology and improves cognitive performance in animal models of Alzheimer's disease (AD). To exclude confounding variables associated with the diet, we crossed 3 × Tg-AD mice (modeling AD neuropathology) with transgenic Fat-1 mice that express the fat-1 gene encoding a PUFA desaturase, which endogenously produces n-3 PUFA from n-6 PUFA. The expression of fat-1 shifted the n-3:n-6 PUFA ratio upward in the brain (+11%, p < 0.001), including docosahexaenoic acid (DHA; +5%, p < 0.001) in 20 month-old mice. The expression of fat-1 decreased the levels …of soluble Aβ42 (−41%, p < 0.01) at 20 months without reducing the level of insoluble forms of Aβ40 and Aβ42 in the brain of 3 × Tg-AD mice. The 3 × Tg-AD/Fat-1 mice exhibited lower cortical levels of both soluble (−25%, p < 0.05) and insoluble phosphorylated tau (−55%, p < 0.05) compared to 3 × Tg-AD mice, but only in 20 month-old animals. Whereas a decrease of calcium/calmodulin-dependent protein kinase II was observed in 3 × Tg-AD/Fat-1 mice (−039%, p < 0.05), altered tau phosphorylation could not be related to changes in glycogen synthase kinase 3β, cyclin-dependent kinase 5, or protein phosphatase type 2A enzymatic activity. In addition, the expression of the fat-1 transgene prevented the increase of glial fibrillary acidic protein (−37%, p < 0.01) observed in 20 month-old 3 × Tg-AD mice. In conclusion, the expression of fat-1 in 3 × Tg-AD mice increases brain DHA and induces biomarker changes that are consistent with a beneficial effect against an AD-like neuropathology. Show more

Keywords: Alzheimer disease, docosahexaenoic acids, n-3 fatty acid desaturase, n-3 polyunsaturated fatty acid, transgenic mice

DOI: 10.3233/JAD-2011-111010

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 853-869, 2011

Authors: Guglielmotto, Michela | Monteleone, Debora | Giliberto, Luca | Fornaro, Michele | Borghi, Roberta | Tamagno, Elena | Tabaton, Massimo

Article Type: Research Article

Abstract: The sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the amyloid-β protein precursor (AβPP) result in the production of the amyloid-β (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of small, soluble aggregates of Aβ42 is the major pathogenic event of Alzheimer's disease (AD). However, the physiologic activity of Aβ peptides is still elusive. Here, we show that expression of BACE1 is regulated by Aβ42 , which augments BACE1 gene transcription through the JNK/c-jun signaling pathway. Of note, Aβ40 has much less effect on BACE1 …expression. These findings unveil a positive feedback loop in which γ-secretase cleavage of AβPP releases a functionally-active peptide, Aβ42 , that promotes BACE1 transcription. Thus, gene expression induced by Aβ42 may have implications in the neuronal dysfunction and degeneration that occurs in AD. Show more

Keywords: Alzheimer's disease, amyloid-β42, BACE1, γ-secretase, JNK/c-jun pathway

DOI: 10.3233/JAD-2011-110884

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 871-883, 2011

Authors: Ashford, J. Wesson | Gere, Emily | Bayley, Peter J.

Article Type: Research Article

Abstract: Memory function generally deteriorates with age, and memory impairments are a common symptom of serious illness such as dementia. Although screening tests are widely used throughout Medicine, they are not yet commonly used to detect memory impairments. The objective of this study was to characterize an audience-based memory test suitable for administration to a large number of individuals simultaneously. A continuous recognition test was developed to assess memory function in audiences using a slide-show in which 50 images were presented, of which 25 were repeated. Audience members responded by recording if an image was a repetition. The test was administered …to a total of 1018 participants at 25 sites with an average audience size of 41 individuals (range = 9–142). A total of 868 individuals aged 40–97 y completed the test appropriately and provided their age, education level, and gender. Recognition memory as measured by discriminability (d′) showed a significant decline with age (40–49 y old, d′ = 3.51; 90–99 y old, d′ = 1.95, p < 0.001) together with a greater than three-fold increase in variability. Individuals with less than 13 y of education had lower scores than those with more education (d′ = 2.13 vs. 2.88, respectively, p < 0.001). These results are consistent with the known effects of age and education on memory. There were no significant effects of gender on test performance. Such memory tests represent a practical and novel approach to screen for the signs of early dementia. Show more

Keywords: Alzheimer's disease, episodic memory, memory screening, object recognition, recognition memory, visual memory

DOI: 10.3233/JAD-2011-110950

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 885-895, 2011

Authors: Greenwood, Tiffany A. | Beeri, Michal S. | Schmeidler, James | Valerio, Daniel | Raventós, Henriette | Mora-Villalobos, Lara | Camacho, Karla | Carrión-Baralt, José R. | Angelo, Gary | Almasy, Laura | Sano, Mary | Silverman, Jeremy M.

Article Type: Research Article

Abstract: We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age). We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4 ± 3.0) and their offspring (n = 188; mean age = 66.4 ± 5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, …attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2 = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2 = 0.50), memory as a cognitive domain (h2 = 0.53), and the overall neuropsychological summary (h2 = 0.42). Heritabilities for sequencing (h2 = 0.42), fluency (h2 = 0.39), abstraction (h2 = 0.36), and the executive functions cognitive domain (h2 = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA. Show more

Keywords: Family studies, hispanic population, neuropsychological phenotype, oldest-old, successful cognitive aging

DOI: 10.3233/JAD-2011-110782

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 897-907, 2011

Authors: Faux, Noel G. | Ellis, Kathryn A. | Porter, Lorine | Fowler, Chris J. | Laws, Simon M. | Martins, Ralph N. | Pertile, Kelly K. | Rembach, Alan | Rowe, Chris C. | Rumble, Rebecca L. | Szoeke, Cassandra | Taddei, Kevin | Taddei, Tania | Trounson, Brett O. | Villemagne, Victor L. | Ward, Vanessa | Ames, David | Masters, Colin L. | the AIBL research group | Bush, Ashley I.

Article Type: Research Article

Abstract: There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects …(+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (−10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate. Show more

Keywords: Alzheimer's disease, biomarker, folate, homocysteine, vitamin B12

DOI: 10.3233/JAD-2011-110752

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 909-922, 2011

Article Type: Correction

DOI: 10.3233/JAD-2011-119011

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 923-923, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110781

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 925-932, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110783

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 933-934, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-27425

Citation: Journal of Alzheimer's Disease, vol. 27, no. 4, pp. 935-944, 2011