Journal of Alzheimer's Disease - Volume 29, issue 3

Authors: Morley, John E. | Farr, Susan A.

Article Type: Review Article

Abstract: Hormesis is the concept that low doses of a toxin can have beneficial effects while high doses are harmful. This is also known as the inverted-U shaped dose-response curve. Hormesis appears to be a universal law for the function of memory mimetics. Amyloid-β protein is widely recognized to be a toxic agent responsible for plaque formation in Alzheimer's disease. In high doses it also produces amnesia. In lower, physiological doses, it enhances long term potentiation and memory. Blocking amyloid-β protein in animals without overproduction of the protein results in amnesia. At low doses, amyloid-β also increases neurite outgrowth, produces presynaptic …enhancement, and may quench oxidative damage. It is postulated that both over- and underproduction of amyloid-β can lead to memory deficits. This is similar to a number of hormonal diseases, e.g., thyroid, where both low and high levels produce disease. Show more

Keywords: Alzheimer's disease, amyloid-β protein, dose response, memory, oxidative damage

DOI: 10.3233/JAD-2011-111928

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 487-492, 2012

Authors: Squitti, Rosanna | Polimanti, Renato

Article Type: Research Article

Abstract: Sporadic Alzheimer's disease (LOAD) is the most common form of dementia and has a high heritability. The genes associated with LOAD explain a small proportion of the genetic contribution to LOAD, leaving several genetic risk factors to be identified. Some authors have suggested a shift from the paradigm “common disease-common gene variants”, which is currently the basis for genome-wide association studies, to a “common disease-multiple rare gene variants” hypothesis aimed at identifying rarer allele variants with large effect size on LOAD onset, suggesting that they may account for the ‘missing’ heritability of LOAD. Recent studies have demonstrated the connection between …copper imbalance and LOAD. Some studies have pointed out the pivotal role of ‘free’ copper, the portion of serum copper non-bound to ceruloplasmin. Free copper has been already identified as a biological marker of Wilson's disease (WD), the paradigmatic disease of free copper toxicosis or accumulation. The ATP7B gene controls free copper levels, and its mutations cause WD. The paradigm shift to “common disease-multiple rare variants” may suitably fit the ATP7B gene; the high heterogeneity of the ATP7B gene may have hidden multiple rare variants with large effect sizes for LOAD. Demonstrating that the ATP7B gene harbors rare variants which may account for some of the missing hereditability of LOAD would support previous evidence of copper involvement in LOAD from a new and totally different perspective and would bring almost immediate benefits in the clinical community in terms of early diagnosis, treatment efficacy, LOAD prevention, and cost savings. Show more

Keywords: Alzheimer's disease, copper, genetic loci, genetic predisposition to disease

DOI: 10.3233/JAD-2011-111991

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 493-501, 2012

Authors: Petrofes Chapa, Rachel D. | Emery, Michael A. | Fawver, Janelle N. | Murray, Ian V.J.

Article Type: Research Article

Abstract: This paper propounds the Amyloids as Sensors and Protectors (ASAP) hypothesis. In this novel hypothesis, we provide evidence that amyloids are capable of sensing dysfunction, and after misfolding, initiate protective cellular responses. Amyloid proteins are initially protective, but chronic stress and overstimulation of the amyloid sensor leads to pathology. This proposed ASAP hypothesis has two sequential stages: (i) sensing, and then (ii) protection. Sensing involves a conformational change of amyloids in response to the cellular environment. The protection aspect translates conformational change into a cellular response via several mechanisms. The most obvious mechanism is that protein misfolding triggers the protective …unfolded protein response, and thus downregulates protein translation and increases chaperone proteins. Other documented responses include metabolic pathways and microRNAs. This ASAP hypothesis has precedence, as amyloid sensors exist (evidenced by CPEB and Sup35), and both prion and amyloid-β sensing redox stress and metals. Our hypothesis expands on previous observations to link sensing with inciting protective cellular response. Furthermore, we substantiate the ASAP hypothesis with previously published evidence from several amyloid diseases. This novel hypothesis links disparate findings in amyloid diseases: metabolic dysfunction, unfolding protein response/chaperones, modification of amyloids, and nutrient or caloric sensing. While this hypothesis can be applied to Alzheimer's disease, it goes beyond the Alzheimer's context. Thus all amyloid proteins can potentially act as sensors of misfolding-causing stress. Finally, this hypothesis will allow for the sensor mechanism and metabolic dysfunction to serve as biomarkers of the diseases as well as therapeutic targets early in disease pathology. Show more

Keywords: β-sheet, ER stress, prion, protein misfolding, uncoupling protein response

DOI: 10.3233/JAD-2012-112015

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 503-514, 2012

Authors: Xing, Yao-Yao | Yu, Jin-Tai | Cui, Wei-Zhen | Zhong, Xiao-Ling | Wu, Zhong-Chen | Zhang, Qun | Tan, Lan

Article Type: Short Communication

Abstract: Variants in the clusterin gene have been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Keywords: Alzheimer's disease, concentration, clusterin, plasma, polymorphism

DOI: 10.3233/JAD-2011-111844

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 515-519, 2012

Authors: Ma, Xiao-Ying | Yu, Jin-Tai | Wu, Zhong-Chen | Zhang, Qun | Liu, Qiu-Yan | Wang, Hui-Fu | Wang, Wei | Tan, Lan

Article Type: Short Communication

Abstract: We conducted a replication study of the 2 genetic variants, rs11754661 and rs2073067, in MTHFD1L that have been recently reported to be associated with late-onset Alzheimer's disease (LOAD) in a genome-wide study in Caucasians. The associations were evaluated in a case-control sample comprising 1,189 Northern Han-Chinese individuals. The rs11754661 polymorphism is associated with LOAD (OR = 1.727; p = 0.016). For rs2073067, LOAD association was found only in APOEε4 carriers (OR = 0.400; p < 0.001). Haplotype analysis revealed the “AC” haplotype increased the risk of developing LOAD (OR = 1.730; p = 0.015). Our findings support a role of …MTHFD1L gene in LOAD. Show more

Keywords: Alzheimer's disease (AD), homocysteine, MTHFD1L, single nucleotide polymorphism

DOI: 10.3233/JAD-2011-111847

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 521-525, 2012

Authors: Dubois, Bruno | Zaim, Mohammed | Touchon, Jacques | Vellas, Bruno | Robert, Philippe | Murphy, Michael F. | Pujadas-Navinés, Francesc | Rainer, Michael | Soininen, Hilkka | Riordan, Henry J. | Kanony-Truc, Claire

Article Type: Research Article

Abstract: New criteria related to prodromal Alzheimer's disease (AD) have been proposed to overcome the issue of heterogeneity of patients with mild cognitive impairment (MCI) and to better define patients in early stage AD. Only few therapeutic trials, if any, have been reported using this newly defined population. The objective of this study was to assess the clinical efficacy and safety of a novel pro-cholinergic drug (V0191) in patients with prodromal AD. Two hundred forty two (242) patients with a diagnosis of prodromal AD were randomized in an approximately 1 : 1 ratio to receive either 1500 mg V0191 or matching …placebo once daily for 24 weeks. Changes in global cognitive functioning were assessed using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog; responder rate as primary efficacy measure). Standardized measures of memory, executive function, attention, functional capacity, and apathy were also obtained. Despite some interesting trends at week 12 and conversion rates favoring V0191, no statistically significant differences in cognitive function between V0191 and placebo were noted. In addition to the absence of drug efficacy on this population, several design features may have hindered this study, including insufficient powering to assess changes in cognition over time, a relatively short duration of treatment, and the lack of validated clinical trial measures designed to assess the prodromal AD population. Lessons learned in AD study design optimization, including those presented in this paper, could be valuable for further investigation with pro-cholinergic drugs such as V0191. Show more

Keywords: Acetylcholine, Alzheimer's disease, cholinergic, drug, MCI, memory, prodromal Alzheimer's disease

DOI: 10.3233/JAD-2012-111370

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 527-535, 2012

Authors: Filippov, Valery | Song, Minwoo Andrew | Zhang, Kangling | Vinters, Harry V. | Tung, Spencer | Kirsch, Wolff M. | Yang, Jun | Duerksen-Hughes, Penelope J.

Article Type: Research Article

Abstract: Ceramide has been suggested to participate in the neuronal cell death that leads to Alzheimer's disease (AD), but its role is not yet well-understood. We compared the levels of six ceramide subspecies, which differ in the length of their fatty acid moieties, in brains from patients who suffered from AD, other neuropathological disorders, or both. We found elevated levels of Cer16, Cer18, Cer20, and Cer24 in brains from patients with any of the tested neural defects. Moreover, ceramide levels were highest in patients with more than one neuropathologic abnormality. Interestingly, the range of values was higher among brains with neural …defects than in controls, suggesting that the regulation of ceramide synthesis is normally under tight control, and that this tight control may be lost during neurodegeneration. These changes, however, did not alter the ratio between the tested ceramide species. To explore the mechanisms underlying this dysregulation, we evaluated the expression of four genes connected to ceramide metabolism: ASMase, NSMase 2, GALC, and UGCG. The patterns of gene expression were complex, but overall, ASMase, NSMase 2, and GALC were upregulated in specimens from patients with neuropathologic abnormalities in comparison with age-matched controls. Such findings suggest these genes as attractive candidates both for diagnostic purposes and for intervening in neurodegenerative processes. Show more

Keywords: Alzheimer's disease, ceramide, neurodegeneration, sphingolipid biosynthesis, sphingolipid regulation

DOI: 10.3233/JAD-2011-111202

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 537-547, 2012

Authors: Wang, Tao | Wang, Chun-Yan | Shan, Zhong-Yan | Teng, Wei-Ping | Wang, Zhan-You

Article Type: Research Article

Abstract: Metal dyshomeostasis in the brain helps promote amyloid-β (Aβ) deposition in Alzheimer's disease (AD). Therefore, targeting the interactions between metal and Aβ is a potential therapeutic approach for AD. The metal chelator, clioquinol (CQ), is thought to reduce Aβ deposits in the AD transgenic mouse brain, and attenuate the clinical symptoms of AD patients. However, whether oral administration of CQ reduces zinc accumulation in Aβ plaques and inhibits the amyloidogenic pathway have not been properly established in AD transgenic mice. By means of autometallographic analysis, we show for the first time that both the number and size of the zinc-containing …plaques were significantly reduced in the brain of amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) double transgenic mice treated with CQ (30 mg/kg/day) orally for 2 months. This was accompanied by a reduction in Aβ burden in the CQ-treated mouse brain. Furthermore, CQ treatment markedly reduced the expression levels of AβPP protein, the β-site of AβPP cleaving enzyme 1 (BACE1), PS1, and the secreted β-secretase-derived fragments of AβPP (sAβPPβ). The present data indicate that CQ is able to reduce zinc accumulation in the neuritic plaques and inhibit amyloidogenic AβPP processing in the AβPP/PS1 mouse brain. Show more

Keywords: AβPP/PS1 transgenic mouse, Alzheimer's disease, amyloid-β, amyloidogenic pathway, clioquinol, zinc

DOI: 10.3233/JAD-2011-111874

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 549-559, 2012

Authors: Grima, Natalie A. | Pase, Matthew P. | Macpherson, Helen | Pipingas, Andrew

Article Type: Research Article

Abstract: Complementary medicine use is becoming increasingly popular with multivitamins being the most commonly used vitamin supplement. Although adequate vitamin and nutrient concentrations are necessary for optimal health and cognitive functioning, there is no scientific consensus as to whether multivitamin use prevents cognitive decline or improves mental functioning. The aim of the present study was to determine if multivitamins can be used efficaciously to improve cognitive abilities. A systematic review of randomized controlled trials was performed. Meta-analysis was performed on those cognitive tests used across the largest number of studies. Multiple electronic databases were searched until July 2011 by two authors. …Randomized, placebo-controlled trials were considered appropriate if they reported on the chronic effects (≥1 month) of oral multivitamin supplementation on any valid cognitive outcomes. Ten trials were included in review (n = 3,200). Meta-analysis indicated that multivitamins were effective in improving immediate free recall memory (SMD = 0.32; 95% CI: 0.09–0.56, p < 0.01) but not delayed free recall memory (SMD = −0.14; 95% CI: −0.43–0.14, p = 0.33) or verbal fluency (SMD = 0.06; 95% CI: −0.05–0.18, p = 0.26). There was no evidence of publication bias or heterogeneity. Other cognitive abilities sensitive to AD pathology, such as executive and visuospatial functions, were found to be under researched. In conclusion, multivitamins were found to enhance immediate free recall memory but no other cognitive domains. Show more

Keywords: Cognition, cognitive, dementia, memory, multivitamin, vitamin, nutrients, meta-analysis, review, pharmacology

DOI: 10.3233/JAD-2011-111751

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 561-569, 2012

Authors: Bakulski, Kelly M. | Dolinoy, Dana C. | Sartor, Maureen A. | Paulson, Henry L. | Konen, John R. | Lieberman, Andrew P. | Albin, Roger L. | Hu, Howard | Rozek, Laura S.

Article Type: Research Article

Abstract: Evidence supports a role for epigenetic mechanisms in the pathogenesis of late-onset Alzheimer's disease (LOAD), but little has been done on a genome-wide scale to identify potential sites involved in disease. This study investigates human postmortem frontal cortex genome-wide DNA methylation profiles between 12 LOAD and 12 cognitively normal age- and gender-matched subjects. Quantitative DNA methylation is determined at 27,578 CpG sites spanning 14,475 genes via the Illumina Infinium HumanMethylation27 BeadArray. Data are analyzed using parallel linear models adjusting for age and gender with empirical Bayes standard error methods. Gene-specific technical and functional validation is performed on an additional 13 …matched pair samples, encompassing a wider age range. Analysis reveals 948 CpG sites representing 918 unique genes as potentially associated with LOAD disease status pending confirmation in additional study populations. Across these 948 sites the subtle mean methylation difference between cases and controls is 2.9%. The CpG site with a minimum false discovery rate located in the promoter of the gene Transmembrane Protein 59 (TMEM59) is 7.3% hypomethylated in cases. Methylation at this site is functionally associated with tissue RNA and protein levels of the TMEM59 gene product. The TMEM59 gene identified from our discovery approach was recently implicated in amyloid-β protein precursor post-translational processing, supporting a role for epigenetic change in LOAD pathology. This study demonstrates widespread, modest discordant DNA methylation in LOAD-diseased tissue independent from DNA methylation changes with age. Identification of epigenetic biomarkers of LOAD risk may allow for the development of novel diagnostic and therapeutic targets. Show more

Keywords: DNA methylation, epigenetics, late onset Alzheimer's disease, prefrontal cortex

DOI: 10.3233/JAD-2012-111223

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 571-588, 2012

Authors: Delano-Wood, Lisa | Stricker, Nikki H. | Sorg, Scott F. | Nation, Daniel A. | Jak, Amy J. | Woods, Steven P. | Libon, David J. | Delis, Dean C. | Frank, Lawrence R. | Bondi, Mark W.

Article Type: Research Article

Abstract: Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented …participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk. Show more

Keywords: Aging, diffusion tensor imaging, memory, mild cognitive impairment, posterior cingulum, white matter

DOI: 10.3233/JAD-2012-102103

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 589-603, 2012

Authors: Reiner, Peggy | Jouvent, Eric | Duchesnay, Edouard | Cuingnet, Rémi | Mangin, Jean-François | Chabriat, Hugues | The Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Differences of cortical morphology between healthy controls (HC), amnestic mild cognitive impairment (MCI), and Alzheimer's disease (AD) have been repeatedly investigated using voxel-based morphometry (VBM). However, the results obtained using mainly VBM remain difficult to interpret as they can be explained by various mechanisms. The aim of the present study was to evaluate the differences of cortical morphology between HC, MCI, and AD patients using a new post-processing method based on reconstruction and identification of cortical sulci. Thirty HC, 33 MCI, and 30 AD patients were randomly selected from the ADNI database. For each subject, cortical sulci were reconstructed and …automatically identified using Brainvisa software. Depth and fold opening of nine large sulci were compared between HC, MCI, and AD patients. Fold opening of parietaloccipital fissure and intraparietal sulcus on both sides strongly differed between the 3 groups, with gradual increase from HC to MCI of about 1 mm and from MCI to AD of about 2 mm (right intraparietal: p = 0.005; left intraparietal: p = 0.004; right parietaloccipital: p = 0.003; left parietaloccipital: p = 0.0009). Results were left unchanged after adjustment for age, gender, and level of education. These variables were also strongly linked to neuropsychological scores, independent of age, gender, and level of education. In the present study, we found important regional differences of cortical morphology with gradual deterioration from HC to MCI to AD. The most important differences were found in parietaloccipital fissure and intraparietal sulcus. Further studies are needed to understand the involved underlying mechanisms. Show more

Keywords: Alzheimer's disease, cortex, cortical sulci, mild cognitive impairment, MRI

DOI: 10.3233/JAD-2012-111622

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 605-613, 2012

Authors: Moon, Minho | Hong, Hyun-Seok | Nam, Dong Woo | Baik, Sung Hoon | Song, Hyundong | Kook, Sun-Young | Kim, Yong Soo | Lee, Jeewoo | Mook-Jung, Inhee

Article Type: Research Article

Abstract: One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of …AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients. Show more

Keywords: 5XFAD mice, Alzheimer's disease, amyloid plaque, calcium-binding proteins, intraneuronal Aβ, pyroglutamate-modified Aβ

DOI: 10.3233/JAD-2011-111778

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 615-628, 2012

Authors: Zhuang, Lin | Wen, Wei | Trollor, Julian N. | Kochan, Nicole A. | Reppermund, Simone | Brodaty, Henry | Sachdev, Perminder

Article Type: Research Article

Abstract: The fornix is a major efferent tract of the hippocampus, a structure critical for normal memory function. However, the role of structural degradation of the fornix in memory dysfunction in mild cognitive impairment (MCI) has remained unclear. We used diffusion tensor tractography to measure microstructural properties of the fornix and the corticospinal tract (CST), as a control tract, in 206 cognitively normal subjects, 76 amnestic MCI (aMCI) and 51 non-amnestic MCI (naMCI) subjects. Hippocampal volumes were measured using deformation-based morphometry. We found significant fractional anisotropy reductions in the left fornix and radial diffusivity (RD) increases in bilateral fornices in aMCI, …but not in naMCI, compared with controls. No significant changes in the CST were found in aMCI subjects, but naMCI subjects showed significantly increased RD and axial diffusivity of the right CST, compared with controls. Increased left fornical RD measure was correlated with poor verbal memory performance in aMCI subjects. In addition, reduced microstructural integrity of the fornix was associated with hippocampal atrophy in aMCI. This study suggests that microstructural alteration of the fornix is a contributor to early episodic memory dysfunction in non-demented individuals. Show more

Keywords: Amnestic mild cognitive impairment, diffusion tensor tractography, fornix, hippocampus, non-amnestic mild cognitive impairment

DOI: 10.3233/JAD-2012-111766

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 629-639, 2012

Authors: Schmand, Ben | Eikelenboom, Piet | van Gool, Willem A. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Using the database of the Alzheimer's Disease Neuroimaging Initiative, we examined the value of neuropsychological assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and FDG-PET scanning with respect to prediction of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We tested the hypothesis that CSF biomarkers and FDG-PET would lose prognostic value when applied in patients older than 75 years, whereas MRI and neuropsychological testing would not. At baseline 175 patients had MCI, mostly amnestic. They were followed during a mean of 2.7 years, and 81 patients converted to AD after a mean of 1.6 years. …Logistic regression analyses showed that neuropsychological assessment and MRI variables predicted conversion with 63 to 67% classification success both in patients younger and older than 75 years, while CSF biomarkers attained this success rate only in patients younger than 75 years. For FDG-PET, this rate was 57% in the total sample. We conclude that the diagnostic yield of different techniques in predicting conversion from MCI to AD is moderate, and that it is affected by age of the subject under study. MRI and neuropsychological assessment remain informative in patients older than 75 years, unlike CSF biomarkers. Show more

Keywords: Alzheimer's disease, amyloid, cerebrospinal fluid, FDG-PET, mild cognitive impairment, MRI, neuropsychological tests, tau protein

DOI: 10.3233/JAD-2012-111703

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 641-648, 2012

Authors: Kim, Nam-Gyoon

Article Type: Research Article

Abstract: The current study examined whether diminished sensitivity to dynamic occlusion in Alzheimer's disease (AD) contributes to reduced capacity to recover 3D shape from motion. Young controls, age-matched elderly controls, and AD patients participated in the study. Participants watched computer simulations of an object, depicted as either transparent or opaque, rotating about the vertical axis against a background rendered in random dot texture. Six geometric solids were graphically simulated, each rendered in three texture densities, against three different levels of background texture densities. Participants identified the displayed object by pointing to the matching wooden object. Young controls were most accurate (79%), …followed by elderly controls (61%) and AD patients (43%). Both control groups identified opaque objects better than transparent objects, but AD patients identified both objects equally poorly. These results demonstrate that dynamic occlusion (i.e., accretion and deletion of optical texture at the occluding edge) facilitates recovery of 3D shape from motion but such capacity is severely impaired in AD. The current results suggest the need for more research into dynamic occlusion, not only as source of information to recover 3D shape from motion, but also as a visual deficit in AD. Show more

Keywords: Alzheimer's disease, dynamic occlusion, projective correspondence, structure-from-motion, 3D shape perception

DOI: 10.3233/JAD-2012-111688

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 649-658, 2012

Authors: Lin, Gui Hua | Lee, Young-Jung | Choi, Dong-Young | Han, Sang Bae | Jung, Jae Kyung | Hwang, Bang Yeon | Moon, Dong Cheul | Kim, Youngsoo | Lee, Myung Koo | Oh, Ki-Wan | Jeong, Heon Sang | Leem, Jae Yoon | Shin, Hwa Kyoung | Lee, Jung Hwa | Hong, Jin Tae

Article Type: Research Article

Abstract: Neuroinflammation is implicated for amyloidogenesis. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects. To investigate thiacremonone's potential effect on anti-neuroinflammation and anti-amyloidogenesis, 4 week old ICR mice were given different doses of thiacremonone (1, 3, and 10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of lipopolysaccharide (LPS) (250 μg/kg/day) at last 7 days of treatment. Our data show thiacremonone decreased LPS-induced memory impairment, glial activation, pro-inflammatory mediators' expression, and amyloidogenesis. In an in vitro study, we obtained …similar results, with thiacremonone (1, 2, and 5 μg/ml) effectively decreased LPS (1 μg/ml)-induced glial activation and inflammatory mediators generation which are implicated in amyloidogenesis. Our data also demonstrated that thiacremonone inhibited LPS-induced amyloidogenesis in cultured astrocytes and microglial BV-2 cells. NF-κB, a critical transcriptional factor regulating not only inflammation but also amyloid-β generation, was inhibited by thiacremonone via blocking of phosphorylation of IκBα in mice brain as well as cultured astrocytes and microglial BV-2 cells. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and amyloidogenesis through inhibition of NF-κB activity, and thus could be applied for intervention of inflammation-related neurodegenerative disease including Alzheimer's disease. Show more

Keywords: Amyloidogenesis, neuroinflammation, NF-κb, thiacremonone

DOI: 10.3233/JAD-2012-111709

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 659-676, 2012

Authors: Lee, Young-Jung | Choi, Dong-Young | Lee, Yong Kyoung | Lee, Yoot Mo | Han, Sang Bae | Kim, Young Hee | Kim, Ki Ho | Nam, Sang-Yoon | Lee, Beom Jun | Kang, Jong-Koo | Yun, Young Won | Oh, Ki-Wan | Hong, Jin Tae

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common form of dementia, is characterized by memory deficits and deposition of amyloid-β (Aβ) in the brain. It has been known that neuroinflammation and oxidative stress are critical factors in the development of AD. 4-O-methylhonokiol, an extract from Magnolia officinalis, is known to have anti-inflammatory and anti-oxidative effects. Thus, we investigated the properties of 4-O-methylhonokiol against progression and development of AD in Tg2576 mice. Tg2576 mice models show memory impairment and AD-like pathological features including Aβ deposition. Oral administration of 4-O-methylhonokiol through drinking water (1 mg/kg in 0.0002% Tween 80) for 12 weeks not only …prevented memory impairment but also inhibited Aβ deposition. In addition, 4-O-methylhonokiol decreased β-secretase activity, oxidative lipid and protein damage levels, activation of astrocytes and microglia cells, and generation of IL-1β and TNF-α with increase of glutathione level in the brain. Our results showed that 4-O-methylhonokiol effectively prevented memory impairment by down-regulating β-secretase activity through inhibition of oxidative stress and neuroinflammatory responses in Tg2576 transgenic mice. Show more

Keywords: 4-O-methylhonokiol, Alzheimer's disease, β-secretase, neuroinflammation, oxidative stress

DOI: 10.3233/JAD-2012-111835

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 677-690, 2012

Authors: Cunnane, Stephen C. | Schneider, Julie A. | Tangney, Christine | Tremblay-Mercier, Jennifer | Fortier, Mélanie | Bennett, David A. | Morris, Martha Clare

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) …were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (−14% and −12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism. Show more

Keywords: Alzheimer's disease, brain lipids, docosahexaenoic acid, free fatty acids, mild cognitive impairment, memory and aging project, oleic acid, omega-3 fatty acids, polyunsaturates, phospholipids

DOI: 10.3233/JAD-2012-110629

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 691-697, 2012

Authors: Di Maria, Emilio | Giorgio, Elisa | Uliana, Vera | Bonvicini, Cristian | Faravelli, Francesca | Cammarata, Sergio | Novello, Maria Cristina | Galimberti, Daniela | Scarpini, Elio | Zanetti, Orazio | Gennarelli, Massimo | Tabaton, Massimo

Article Type: Research Article

Abstract: The complex network of neurotrophic factors is supposed to play a role in neurodegeneration, but the effect of variations in their coding genes on susceptibility to sporadic Alzheimer's disease is not established. The mature form of nerve growth factor (NGF) derives from a precursor, proNGF, which was recently discovered to exert crucial functions in brain. We designed a case-control association study to test the hypothesis as to whether polymorphisms located in the proNGF genomic region influence the liability to Alzheimer's disease and its prodromal form, mild cognitive impairment. Three independent case-control samples, with individuals aged >60 years, were collected in …Italian Alzheimer Units. One polymorphism located in the proNGF region, rs6330, demonstrated a minor allele frequency >5% and was used in the association study. The minor allele of rs6330 was more frequent in patients from the three sample series as compared to respective normal controls. Multivariate logistic regression showed a significant association under the dominant model in one cohort (OR 1.83, 95% CI 1.00–3.54) and in the pooled case-control sample (OR 1.47, 95% CI 1.03–2.08). These findings further suggest that proNGF may play a role in Alzheimer-type neurodegeneration and that genetic variations in the NGF locus may influence the occurrence of sporadic, late-onset Alzheimer's disease. Show more

Keywords: Alzheimer's disease, APOE, association study, mild cognitive impairment, NGF, NGFB, proNGF

DOI: 10.3233/JAD-2012-112006

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 699-705, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-112007

Citation: Journal of Alzheimer's Disease, vol. 29, no. 3, pp. 707-709, 2012