Journal of Alzheimer's Disease - Volume 31, issue 4

Authors: Xia, Weiming | Wong, Stephen T. | Hanlon, Eugene | Morin, Peter

Article Type: Review Article

Abstract: The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat (LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the γ-secretase era. γ-Secretase modulators, by definition, only block the γ-secretase cleavage of amyloid-β protein precursor (AβPP) to generate the longer, 42-residue amyloid-β (Aβ42 ) without changing the production of total Aβ. The first generation GSMs were shown to block Aβ42 generation while increasing Aβ38 . The non-steroidal anti-inflammatory drug, Tarenflurbil, binds to AβPP and shifts the cleavage site from Aβ42 to Aβ38 . In addition, Tarenflurbil does not affect the …γ-secretase cleavage of Notch. Even before the failed clinical trials of Tarenflurbil, second generation GSMs had emerged, and some of these GSMs interact with presenilin, which carries the active site of the γ-secretase. While second generation GSMs are pharmacologically superior to first generation GSMs, in vivo Aβ profiles (decreased levels of Aβ38 , Aβ40 , and Aβ42 ) in animals treated with potent GSMs are strikingly different from those in cultured cells. Thus, the unique pharmacologic properties of new GSMs and their mechanisms of action need to be elucidated in order to avoid the fate of Tarenflurbil. It is critical to understand how GSMs shift the “end” in vivo, i.e., shifting the γ-secretase cleavage at the C-terminal end of Aβ. In view of the myriad effects of candidate GSMs on Aβ production in cells and animals, drug development would benefit from better definition of the target-GSM interaction and physiological function of shorter Aβ peptides. Show more

Keywords: Alzheimer's disease, amyloid, inhibitor, modulator, Notch, presenilin, secretase

DOI: 10.3233/JAD-2012-120751

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 685-696, 2012

Authors: Pérez-Martínez, Francisco C. | Carrión, Blanca | Ceña, Valentín

Article Type: Review Article

Abstract: Nanoparticles represent an alternative to viral vectors for genetic material transfer to the nervous system. However, to increase transfection efficiency in the central nervous system and to decrease toxicity, the design of nanoparticles needs to be improved to enhance blood-brain barrier crossing and endosomal escape. This paper reviews the strategies used to solve these difficulties and covers the use of various nanoparticles including natural inorganic particles, natural polymers, cationic lipids, polyethylenimine derivatives, dendrimers, and carbon-based nanoparticles. The effectiveness, both in vivo and in vitro, of each method to deliver genetic material to neural tissue is discussed.

Keywords: Blood-brain barrier, dendrimers, gene transfer, nanoparticles, neurons, siRNA

DOI: 10.3233/JAD-2012-120661

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 697-710, 2012

Authors: Figueiro, Mariana G. | Hamner, Robert | Higgins, Patricia | Hornick, Thomas | Rea, Mark S.

Article Type: Short Communication

Abstract: The absence of daily robust light-dark exposure patterns may contribute to sleep disturbances in persons with Alzheimer's disease and related dementias (ADRD). Personal light-dark and activity-rest patterns were measured for healthy older adults and for persons with ADRD. Persons with ADRD experienced lower light levels, exhibited lower activity levels, and had greater levels of circadian disruption than healthy older adults during winter. Seasonal differences were observed for persons with ADRD; lower levels of light exposure and greater levels of circadian disruption were seen during the winter than during the summer, although activity levels did not differ for the two seasons.

Keywords: Alzheimer's disease, circadian, circadian dysregulation, circadian light, phasor magnitude

DOI: 10.3233/JAD-2012-120484

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 711-715, 2012

Authors: von Arnim, Christine A.F. | Herbolsheimer, Florian | Nikolaus, Thorsten | Peter, Richard | Biesalski, Hans K. | Ludolph, Albert C. | Riepe, Matthias | Nagel, Gabriele | the ActiFE Ulm study group

Article Type: Research Article

Abstract: Oxidative stress is believed to play a central role in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease. Antioxidants may prevent the onset AD as high dietary intake of vitamin C and E were reported to be associated with lower risk of the disease. The objective of this study was to evaluate the serum levels of antioxidants in persons with mild dementia to test whether it is associated with lower levels of antioxidants in a cross-sectional study in the population of the “Activity and Function in the Ederly in Ulm” (ActiFE) study. Main exposure measures were vitamin C, vitamin …E, β-carotene, lycopene, and coenzyme Q10 as analyzed by HPLC. Main outcome measures were mild cognitive impairment among 74 mildly demented compared to 158 age- and gender-matched controls. We found that blood vitamin C and β-carotene concentrations were significantly lower in demented than in control persons even after adjusting for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption (3rd versus 1st tertile: OR: 0.29, 95% CI, 0.09–0.96 and 0.13, 95% CI, 0.03–0.55, respectively). No associations were found for vitamin E, lycopene, and coenzyme Q10. Our findings suggest an association of vitamin C and β-carotene with dementia. However this is limited to the cross-sectional character of our study and longitudinal data will give further insight into this association. Show more

Keywords: Antioxidants, beta carotene, dementia, older population, oxidative stress, vitamin C

DOI: 10.3233/JAD-2012-120634

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 717-724, 2012

Authors: Exley, Christopher | House, Emily | Polwart, Anthony | Esiri, Margaret M.

Article Type: Research Article

Abstract: The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer's disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloidβ deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of …both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu : Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that in individuals with moderate to severe amyloid pathology low brain copper is a predisposition to developing dementia. Show more

Keywords: Aluminum, Alzheimer's disease, amyloid-β, congophilic amyloid angiopathy, copper, iron, human brain tissue, senile plaque

DOI: 10.3233/JAD-2012-120766

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 725-730, 2012

Authors: Seripa, Davide | Bizzarro, Alessandra | Pilotto, Andrea | Palmieri, Orazio | Panza, Francesco | D'Onofrio, Grazia | Gravina, Carolina | Archetti, Silvana | Daniele, Antonio | Borroni, Barbara | Padovani, Alessandro | Masullo, Carlo

Article Type: Research Article

Abstract: The aim of this study was to investigate the apolipoprotein E (APOE) chromosomal region in frontotemporal lobar degeneration (FTLD), and in particular in primary progressive aphasia (PPA) and the behavioral variant frontotemporal dementia (bvFTD). To this aim, we selected three single-nucleotide polymorphisms (SNPs) rs2075650 and rs157590 (TOMM40), and rs1064725 (APOC1), representative of the linkage disequilibrium (LD) blocks at the 19q13-q13.2 chromosomal region. The SNPs rs429358 and rs7412 forming the APOE polymorphism were also included in the study. The analysis was made in 282 patients with a clinical diagnosis of sporadic FTLD, namely 207 bvFTD and 75 PPA, and 296 cognitively …healthy control subjects. LD (r2 = 0.35) between TOMM40 (rs2075650) and APOC1 (rs1064725) was observed in PPA, but not in controls and in bvFTD. Inside this region of 26.9 kb, LD (r2 ≥ 0.50) between TOMM40 (rs2075650) and APOE (rs429358) was observed in bvFTD and in controls, but not in PPA. Inside this region of 16.3 kb, LD (r2 = 0.14) between TOMM40 (rs157590) and APOE (rs429358) was observed in PPA, but not in bvFTD and in controls. Although the genetics of PPA and bvFTD needs further investigation, our results suggested the presence of a different genetic background underlying PPA and bvFTD at the 19q13-q13.2 chromosomal region. Show more

Keywords: APOC1, APOE E, behavioral variant of frontotemporal dementia, frontotemporal lobar degeneration, primary progressive aphasia, TOMM40

DOI: 10.3233/JAD-2012-120403

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 731-740, 2012

Authors: Deramecourt, Vincent | Lebert, Florence | Maurage, Claude-Alain | Fernandez-Gomez, Francisco-Jose | Dujardin, Simon | Colin, Morvane | Sergeant, Nicolas | Buée-Scherrer, Valérie | Clot, Fabienne | Ber, Isabelle Le | Brice, Alexis | Pasquier, Florence | Buée, Luc

Article Type: Research Article

Abstract: MAPT mutations cause autosomal dominant frontotemporal lobar degeneration. These diseases are characterized by considerable heterogeneity in their clinical, neuropathological, and biochemical presentations. We describe the full characterization of a family with autosomal dominant frontotemporal lobar degeneration caused by a novel MAPT mutation. Clinical, imaging, neuropathological, and biochemical data are presented. The proband was a woman who died at 85 years old, 25 years after the onset of a slowly progressive and isolated anarthria and opercular syndrome. The pathological examination of her brain showed marked atrophy of primary motor and premotor cortices, associated with predominant neuronal tau-positive lesions mimicking Pick bodies. …At the biochemical level, the six tau isoforms aggregate to display a pathological triplet at 60, 64, and 69 kDa. Two of her sons presented at 48 and 50 years old with a right temporal variant of frontotemporal degeneration characterized by severe prosopagnosia, semantic impairment, and behavioral modifications. In these three patients, the molecular analysis of MAPT showed the c.1945C>T mutation on exon 11 resulting in the P332S substitution in tau sequence. This mutation changes the PGGG motif of the third repeat domain of the protein and therefore reduces the ability of tau to bind microtubule. From a clinical point of view, this mutation is associated with considerable intrafamilial phenotypic variation. Show more

Keywords: Frontotemporal lobar degeneration, FTDP-17, MAPT, Pick body, progressive anarthria, semantic dementia, tau protein

DOI: 10.3233/JAD-2012-120160

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 741-749, 2012

Authors: Arlt, Sönke | Schwedhelm, Edzard | Kölsch, Heike | Jahn, Holger | Linnebank, Michael | Smulders, Yvo | Jessen, Frank | Böger, Rainer H. | Popp, Julius

Article Type: Research Article

Abstract: Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42 ), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as …CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis. Show more

Keywords: Alzheimer's disease, asymmetric dimethylarginine, cerebrospinal fluid, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine

DOI: 10.3233/JAD-2012-112138

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 751-758, 2012

Authors: Laakso, Tiina | Muggalla, Pranuthi | Kysenius, Kai | Laurén, Juha | Paatero, Anja | Huttunen, Henri J. | Airaksinen, Matti S.

Article Type: Research Article

Abstract: Neuronal LRRTM3 (leucine-rich repeat transmembrane 3) protein has been reported to promote amyloid-β protein precursor (AβPP) processing and LRRTM3 is a candidate gene in late-onset Alzheimer's disease. To address the role of LRRTM3 in AβPP processing and amyloid-β (Aβ) production in vivo, we analyzed amyloidogenic processing of AβPP in the brains of LRRTM3-deficient mice and transgenic AβPP/PS1 mice with or without LRRTM3. We did not find differences between the genotypes in the levels of Aβ or AβPP C-terminal fragments indicating that LRRTM3 is not an essential regulator of Aβ production in adult mice. Moreover, Aβ levels in primary cortical neurons …were similar between the genotypes, indicating that LRRTM3 is not required for Aβ generation in developing mice. Show more

Keywords: Amyloid-β protein precursor, BACE1, LRR-domain, neurexin, synaptogenic

DOI: 10.3233/JAD-2012-120193

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 759-764, 2012

Authors: Zeng, Yan | Liu, Yakun | Wu, Mianyun | Liu, Jun | Hu, Qi

Article Type: Research Article

Abstract: 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a brain-derived neurotrophic factor (BDNF) mimetic to selectively activate the tropomyosin-related kinase B (TrkB) with high affinity. We have previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. The present study assessed the effectiveness of 7,8-DHF on age-related declines in fear memories and amygdalar synaptic plasticity. We found that Sprague Dawley male rats began to show significant deficits in the acquisition and retention of memories for contextual and cued fear conditioning, as well as the reduction of BDNF, TrkB, and phosphorylated TrkB at the age of …25 months. Therefore, rats at 24 months old received intraperitoneal administration of either 7,8-DHF (5 mg/kg, i.p.) or vehicle once daily for a consecutive 4 weeks. At the end of treatment period, cognitive performance, amygdalar synaptic plasticity, synaptogenesis, and the phosphorylation of several proteins crucial to synaptic plasticity were evaluated. The results show that chronic 7,8-DHF treatments significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased spine density and number in several brain regions that process fear memory including the amygdala, hippocampus, and prefrontal cortex, facilitated basolateral amygdalar synaptic plasticity, and in turn prevented performance in fear conditioning tasks from declining. Our results thus confirm a critical role for TrkB signaling activation by 7,8-DHF in preventing age-related declines in fear learning and memory and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in reversing age-related memory impairment. Show more

Keywords: 7,8-dihydroxyflavone, aging, learning and memory, synaptic plasticity, TrkB

DOI: 10.3233/JAD-2012-120886

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 765-778, 2012

Authors: Yildiz-Unal, Aysegul | Korulu, Sirin | Karabay, Arzu

Article Type: Research Article

Abstract: The calcium-activated proteolytic enzyme calpain is one of the key proteins that can directly or indirectly drive neurons into apoptosis. The indirect way is through cyclin dependent kinase 5 (CDK5), a non-mitotic kinase, which is upregulated through calpain overactivation and followed by a subsequent increase in p53 and active caspase-3 levels under neurodegenerative conditions. The direct way is the upregulation of p53 by calpain itself, since p53 is a substrate for it. SpeedyRINGO is an atypical cell cycle regulator that has been shown to have protective effects in mitotic cells against apoptosis by inhibiting caspase-3 activation when p53 is present. …Our aim was to reveal possible protective effects of SpeedyRINGO against calpain-induced caspase-3 activation in neurons which is crucial in terms of providing novel insights in preventing the caspase-3 activation cascade in neurodegeneration. For this reason, mRNA and protein levels were analyzed by qRT-PCR, western blotting, and immunofluorescence. We show that calpain overactivation leads to the upregulation of p53 and a subsequent increase in active caspase-3 level, indicating activation of apoptotic machinery in neurons. This calpain-directed caspase-3 activation upon upregulation of p53 is inhibited by the expression of SpeedyRINGO in rat hippocampal neurons. Therefore, SpeedyRINGO acts as a savior for neurons that are under apoptotisis due to caspase-3 activation. Show more

Keywords: Calpain, caspase, cdk, neuron, p53, SpeedyRINGO

DOI: 10.3233/JAD-2012-120652

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 779-791, 2012

Authors: van Abel, Daan | Michel, Omar | Veerhuis, Rob | Jacobs, Marlies | van Dijk, Marie | Oudejans, Cees B.M.

Article Type: Research Article

Abstract: STOX1A is a transcription factor which is functionally and structurally similar to the forkhead box protein family. STOX1A has been shown to be associated with pre-eclampsia, a pregnancy associated disease, and to have potential implications in late onset Alzheimer's disease. However, the exact function of STOX1A and its target genes are still largely unknown. Therefore, in this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. Additionally, we show that CNTNAP2 expression is downregulated in the hippocampus of …Alzheimer's disease patients where STOX1A expression has been shown to be upregulated. In conclusion, these results further indicate the potential involvement of STOX1A and its target genes in the etiology of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, CNTNAP2, FOXP2, myelination, STOX1A

DOI: 10.3233/JAD-2012-120472

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 793-800, 2012

Authors: Zhang, Ru | Xue, Guizhen | Wang, Shaodeng | Zhang, Lihong | Shi, Changjie | Xie, Xin

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the AβPP/PS1 transgenic mouse model is a commonly used experimental model to mimic the pathological and cognitive impairments in AD. As a classic method to evaluate spatial learning and memory, the Morris water maze is widely applied to study the cognitive deficits in rodent AD models. However, the assay procedure is relatively complicated and requires a properly equipped environment. The novel object recognition test is a relatively simple and straightforward method to test working memory in rodents. However, whether the latter can be used as a common tool for evaluating the …therapeutic effects of drugs in the AβPP/PS1 transgenic AD mouse model remains unclear. In the present study, we assessed the cognitive impairment of AβPP/PS1 AD mice with the novel object recognition test. In parallel, Morris water maze was performed and compared with the novel object recognition study. Both assays worked equally well in evaluating the cognitive defect of AβPP/PS1 mice. Furthermore, we drew similar conclusions from the novel object recognition assay as from the Morris water maze in assessing the therapeutic effects of two previously reported compounds, donepezil and naltrindole, on AD. We found the novel object recognition to be a facile assay with almost no stress to mice and think it could be used as an ideal primary screening assay to evaluate drug effects on AβPP/PS1 AD model. Show more

Keywords: AβPP/PS1, Alzheimer's disease, donepezil, Morris water maze, naltrindole, novel object recognition

DOI: 10.3233/JAD-2012-120151

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 801-812, 2012

Authors: Jansen, Diane | Janssen, Carola I.F. | Vanmierlo, Tim | Dederen, Pieter J. | van Rooij, Daan | Zinnhardt, Bastian | Nobelen, Cindy L.M. | Janssen, Anna-Lena | Hafkemeijer, Anne | Mutsaers, Martina P.C. | Doedée, Anne M.C.M. | Kuipers, Almar A.M. | Broersen, Laus M. | Mulder, Monique | Kiliaan, Amanda J.

Article Type: Research Article

Abstract: Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-β deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AβPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AβPP-PS1 mice compared to age-matched wild-type animals, …but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AβPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology. Show more

Keywords: Aging, Alzheimer's disease, amyloid-β, cholesterol, glucose transporter type-1, hippocampus, liver X receptor, synapse, synaptophysin, T0901317, transgenic mice

DOI: 10.3233/JAD-2012-120298

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 813-826, 2012

Authors: Yang, Jing | Pan, PingLei | Song, Wei | Shang, Hui-Fang

Article Type: Research Article

Abstract: Cumulative evidence of gray matter abnormalities in semantic dementia (SD) has been reported using voxel-based morphometry (VBM). However, these studies have not been reviewed quantitatively. To estimate gray matter changes in SD quantitatively, we systematically searched whole-brain VBM studies comparing SD patients with healthy controls in the PubMed, ISI Web of Science, and EMABSE databases from January 1990 to August 2011. Coordinates with significant differences between the gray matter volumes of SD patients and healthy controls were extracted from clusters. Meta-analysis was performed using anatomic likelihood estimation. Seven studies, with 68 SD patients and 167 healthy controls, were included. Gray …matter volume reductions were found in bilateral fusiform and inferior temporal gyri, extending to the medial portion of the temporal lobes (including amygdala and parahippocampal gyri), left temporal pole, middle temporal gyrus, and caudate. No significant increase in gray matter volume was found. Our findings provide strong evidence of atrophy in bilateral temporal lobes with predominate impairment on the left side, parahippocampal gyrus/amygdala, and left caudate, representing the pathophysiology of SD. Show more

Keywords: Frontotemporal lobar degeneration, magnetic resonance imaging, meta-analysis, semantic dementia

DOI: 10.3233/JAD-2012-120736

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 827-833, 2012

Authors: Paillard-Borg, Stéphanie | Fratiglioni, Laura | Xu, Weili | Winblad, Bengt | Wang, Hui-Xin

Article Type: Research Article

Abstract: The purpose of this study was to test the hypothesis that an active lifestyle delays age at dementia onset. This study included 388 incident dementia cases (DSM-III-R criteria) that developed over a 9-year follow-up period among 1,375 baseline dementia-free community dwellers with good cognitive function (MMSE >23) (mean age = 81.2) from the Kungsholmen Project. An active lifestyle was defined as participation in mental, physical, or social activity. We used linear regression models to estimate influence of baseline active lifestyle on age at onset of incident dementia and general linear models to estimate mean age at dementia onset. Age at …onset of dementia was significantly older in persons who had higher levels of participation in mental, physical, or social activity (β: 0.18, 0.29 and 0.23 respectively, p < 0.001 for all the activities) independent of education, medical condition, functional status, and other confounders including APOE. When the three types of activities were integrated into an index, we found that the broader the spectrum of participation in the activities, the later the onset of disease (β = 0.93, p = 0.01 for participating in two activities, and β = 1.42, p < 0.001 for three activities). There were 17 months difference in mean age at dementia onset between the inactive group and the most active group. An active lifestyle operates as a protective factor for dementia by delaying the clinical onset of the disease. These findings highlight the relevance of encouraging old adults to have active lifestyles, which could have a great impact on public health. Show more

Keywords: Age at dementia onset, dementia, leisure activities, lifestyle, old adults

DOI: 10.3233/JAD-2012-120724

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 835-842, 2012

Authors: Sanchez-Ramos, Juan | Cimino, Cynthia | Avila, Ross | Rowe, Amanda | Chen, Ren | Whelan, Glenn | Lin, Xiaoyang | Cao, Chuanhai | Ashok, Raj

Article Type: Research Article

Abstract: Human granulocyte colony-stimulating-factor (G-CSF) is widely used for treatment of neutropenia and to mobilize stem/progenitor cells for bone marrow transplantation. In studies of thousands of healthy donor subjects treated with G-CSF to mobilize stem/progenitor cells, the side-effect profile has been reported to be mild and reversible. In pre-clinical studies, G-CSF was reported to improve spatial learning performance and to markedly reduce amyloid deposition in hippocampus and entorhinal cortex in a murine model of Alzheimer's disease (AD). The present study investigated the effects of a five day schedule of G-CSF administration on tolerability, safety, and cognition in eight patients with mild …to moderate stage AD. A double-blind placebo control, cross-over design was implemented. Treatment with G-CSF did not result in serious adverse events. The most common and expected side effects were transient increases in white blood cell count, myalgias and diffuse aching that improved with non-steroidal anti-inflammatory medications. Of a battery of cognitive tests administered using the CANTAB computerized system, only the mean paired associate learning (PAL total trials adjusted) was significantly improved at the final visit of the study compared to baseline values (p < 0.05). There were no significant differences in amyloid-β1-42 levels in cerebrospinal fluid measured two weeks after G-CSF and two weeks after placebo treatments. In conclusion, administration of G-CSF in a dosage regimen commonly used for bone marrow donors was well tolerated and safe, and provided a signal of positive change in a hippocampal-dependent task of cognitive performance. Show more

Keywords: Alzheimer's disease, amyloid-β, computer assisted neuropsychological battery, cytokines, filgrastim, granulocyte-colony stimulating factor, NEUPOGEN®, paired-associate learning

DOI: 10.3233/JAD-2012-120196

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 843-855, 2012

Authors: Chou, Mei-Chuan | Chen, Chun-Hung | Liu, Ching-Kuan | Chen, Su-Hwei | Wu, Shyh-Jong | Yang, Yuan-Han

Article Type: Research Article

Abstract: The aim of this small pilot study was to evaluate the association between plasma concentrations of rivastigmine and its metabolite, NAP 226-90, and cognitive function in patients with Alzheimer's disease (AD). Rivastigmine-treated AD patients, who had been maintained on a fixed regimen of twice daily rivastigmine (6 to 12 mg/d) for ≥6 months, were eligible for evaluation. The assessments included Cognitive Assessment Screening Instrument (CASI) and Clinical Dementia Rating scale, conducted at baseline and at 6-month follow-up. The 9 subdomains of CASI at baseline and follow-up were analyzed in relation to the plasma concentrations of rivastigmine and NAP 226-90, as …measured by capillary electrophoresis. Logistic regression was performed to adjust for age, gender, education level, apolipoprotein E ε4 genotype status, and baseline CASI score to investigate the association between plasma rivastigmine and NAP 226-90 concentrations and the cognitive response. The total sample consisted of 53 clinically diagnosed AD patients taking rivastigmine only at doses of 6 mg to 9 mg/d because of intolerability at 12 mg/d. Higher rivastigmine concentration was significantly associated with improved or preserved short-term memory and worsened abstraction/judgment (p < 0.05), but not with changes in other domains (p > 0.05). Higher NAP 226-90 concentration was significantly associated with worsened abstraction/judgment (p < 0.05), but not with changes in other domains. Higher plasma rivastigmine concentration was significantly associated with improved or preserved short-term memory but worsened abstraction/judgment. An optimal concentration of rivastigmine should be quantified for each patient because of differential cognitive responses. Show more

Keywords: Alzheimer's disease, cognitive assessment screening instrument, rivastigmine, Taiwanese

DOI: 10.3233/JAD-2012-120109

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 857-864, 2012

Authors: Sancesario, Giulia M. | Cencioni, Maria T. | Esposito, Zaira | Borsellino, Giovanna | Nuccetelli, Marzia | Martorana, Alessandro | Battistini, Luca | Sorge, Roberto | Spalletta, Gianfranco | Ferrazzoli, Davide | Bernardi, Giorgio | Bernardini, Sergio | Sancesario, Giuseppe

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomers are heterogeneous and instable compounds of variable molecular weight. Flow cytometry and fluorescence resonance energy transfer (FRET)-based methods allow the simultaneous detection of Aβ oligomers with low and high molecular weight in their native form. We evaluated whether an estimate of different species of Aβ oligomers in the cerebrospinal fluid (CSF) with or without dilution with RIPA buffer could be more useful in the diagnosis of Alzheimer's disease (AD) than the measurement of Aβ42 monomers, total tau (t-tau), and phosphorylated tau (p-tau). Increased t-tau (p < 0.01) and p-tau (p < 0.01), and decreased Aβ42 …(p < 0.01), were detected in the CSF of patients with AD (n = 46), compared to patients with other dementia (OD) (n = 35) or with other neurological disorders (OND) (n = 56). In native CSF (n = 137), the levels of Aβ oligomers were lower (p < 0.05) in AD than in OD and OND patients; in addition, the ratio Aβ oligomers/p-tau was lower in AD than in OD (p < 0.01) and OND (p < 0.05) patients, yielding a sensitivity of 75% and a specificity of 64%. However, in CSF diluted with RIPA (n = 30), Aβ oligomers appeared higher (p < 0.05) in AD than in OND patients, suggesting they become partially disaggregated and more easily detectable after RIPA. In conclusion, FRET analysis in native CSF is essential to correctly determine the composition of Aβ oligomers. In this experimental setting, the simultaneous estimate of low and high molecular weight Aβ oligomers is as useful as the other biomarkers in the diagnosis of AD. The low amount of Aβ oligomers detected in native CSF of AD may be inversely related to their levels in the brain, as occurs for Aβ monomers, representing a biomarker for the amyloid pathogenic cascade. Show more

Keywords: Aβ42, Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, flow cytometry, fluorescence resonance energy transfer, FRET, oligomers

DOI: 10.3233/JAD-2012-120211

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 865-878, 2012

Authors: Fuentealba, Jorge | Dibarrart, Andrea | Saez-Orellana, Francisco | Fuentes-Fuentes, María Cecilia | Oyanedel, Carlos N. | Guzmán, José | Perez, Claudia | Becerra, José | Aguayo, Luis G.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by the presence of different types of extracellular and neurotoxic aggregates of amyloid-β (Aβ). Recently, bioactive compounds extracted from natural sources showing neuroprotective properties have become of interest in brain neurodegeneration. We have purified, characterized, and evaluated the protective potential of one extract enriched in polyphenols obtained from Aristotelia chilensis (MQ), a Chilean berry fruit, in neuronal models of AD induced by soluble oligomers of Aβ1-40 . For example, using primary hippocampal cultures from rats (E18), we observed neuroprotection when the neurons were co-incubated with Aβ (0.5 μM) plus MQ for 24 h (Aβ = …23 ± 2%; Aβ + MQ = 3 ± 1%; n = 3). In parallel, co-incubation of Aβ with MQ recovered the frequency of Ca2+ transient oscillations when compared to neurons treated with Aβ alone (Aβ = 72 ± 3%; Aβ + MQ = 86 ± 2%; n = 5), correlating with the changes observed in spontaneous synaptic activity. Additionally, MAP-2 immunostaining showed a preservation of the dendritic tree, suggesting that the toxic effect of Aβ is prevented in the presence of MQ. A new complex mechanism is proposed by which MQ induces neuroprotective effects including antioxidant properties, modulation of cell survival pathways, and/or direct interaction with the Aβ aggregates. Our results suggest that MQ induces changes in the aggregation kinetics of Aβ producing variations in the nucleation phase (Aβ: k1 = 2.7 ± 0.4 × 10−3 s−1 MQ: k1 = 8.3 ± 0.6 × 10−3 s−1 ) and altering Thioflavin T insertion in β-sheets. In conclusion, MQ induces a potent neuroprotection by direct interaction with the Aβ aggregates, generating far less toxic species and in this way protecting the neuronal network. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, antioxidant, hippocampal neurons, maqui, nutraceuticals, polyphenols

DOI: 10.3233/JAD-2012-120229

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 879-889, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-120230

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 891-893, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-31422

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 895-906, 2012