Journal of Alzheimer's Disease - Volume 27, issue 1

Authors: Pac-Soo, Chen | Lloyd, Dafydd G. | Vizcaychipi, Marcela P. | Ma, Daqing

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease commonly seen in the elderly and is characterized by progressive cognitive and physical decline. Current understanding of AD pathogenesis revolves around amyloid-β peptide (Aβ), a product of the sequential proteolytic cleavage of the transmembrane amyloid-β protein precursor (AβPP) by β- and γ-secretase, enzymes found predominantly in the cholesterol rich micro domains of the cell membrane. Several risk factors for AD are associated with cholesterol metabolism, including dyslipidaemia, coronary artery and cerebrovascular disease. Statins are widely prescribed for their cholesterol lowering ability and show a favorable side effect profile overall. By competitive inhibition …of hydroxymethyl co-enzyme A-reductase, statins reduce the production of cholesterol and isoprenoid intermediates including geranylgeranyl and farnesyl pyrophosphate. These isoprenoids modify recently translated proteins such as small GTPase molecules that are essential in numerous cell-signaling pathways, including vesicular trafficking and inflammation. In experimental models of AD, statins reduce the production of Aβ by disrupting secretase enzyme function and by reducing neuroinflammation. Furthermore, epidemiological studies suggest that statins may reduce the incidence of AD. Consequently, statins, secondary of their anti-hypercholesterolaemic, plieotropic and anti-inflammatory effects, are being investigated for a potential therapeutic role. This review will discuss evidence for the role of statins in the treatment and prevention of AD neurodegeneration. Show more

Keywords: Alzheimer's disease, cholesterol, inflammation, microglial activation, statin

DOI: 10.3233/JAD-2011-110524

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 1-10, 2011

Authors: Didic, Mira | Barbeau, Emmanuel J. | Felician, Olivier | Tramoni, Eve | Guedj, Eric | Poncet, Michel | Ceccaldi, Mathieu

Article Type: Research Article

Abstract: Diagnosis of Alzheimer's disease (AD) in its earliest stages becomes increasingly important as disease modifying agents are being developed. In this area of research, many clinical and neuroimaging studies focus on markers of hippocampal dysfunction. However, during the “transentorhinal stage” of AD, neurofibrillary tangles (NFT), related to tau protein pathology, develop in the anterior subhippocampal (perirhinal/entorhinal) cortex before the hippocampus. NFT are tightly correlated with clinical symptoms. Therefore, an accurate understanding of the behavioral correlate of transentorhinal dysfunction could critically contribute to the early diagnosis of the disease. Recent findings from studies in animals and human brain-damaged patients suggest that …the anterior subhippocampal region, functionally integrated into an anterior mesiotemporal network, is involved in object based context-free memory. In this article, we evaluate the hypothesis according to which tau deposition in the anterior subhippocampal region during the earliest stages of the most common form of AD, with predominant MTL dysfunction, will lead to dysfunction of neural networks implicated in context-free memory. We challenge the view that impaired episodic memory is the hallmark of early AD. Instead, a model that integrates the localization and temporal sequence of NFT within the mesial temporal lobe (MTL) is proposed. Paralleling the development of NFT in anterior subhippocampal areas, impaired context-free, object-based, memory could be the first detectable sign in AD. In a subsequent, “hippocampal” stage, context-rich, episodic and spatial memory, becomes altered as well. The question as to the “episodic” nature of “episodic memory tasks” is also addressed. Show more

Keywords: Alzheimer's disease, amnesia, entorhinal cortex, hippocampus, memory, mesial temporal lobe, perirhinal cortex

DOI: 10.3233/JAD-2011-110557

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 11-22, 2011

Authors: Kou, Jinghong | Kim, HongDuck | Pattanayak, Abhinandan | Song, Min | Lim, Jeong-Eun | Taguchi, Hiroaki | Paul, Sudhir | Cirrito, John R. | Ponnazhagan, Selvarangan | Fukuchi, Ken-ichiro

Article Type: Research Article

Abstract: Accumulation of amyloid-β protein (Aβ) in the brain is thought to be a causal event in Alzheimer's disease (AD). Immunotherapy targeting Aβ holds great promise for reducing Aβ in the brain. Here, we evaluated the efficacy and safety of anti-Aβ single-chain antibody (scFv59) delivery via recombinant adeno-associated virus (rAAV) on reducing Aβ deposits in an AD mouse model (TgAβPPswe/PS1dE9). First, delivery of scFv59 to the brain was optimized by injecting rAAV serotypes 1, 2, and 5 into the right lateral ventricle. Symmetrical high expression of scFv59 was found throughout the hippocampus and partly in the neocortex in both hemispheres via …rAAV1 or rAAV5, while scFv59 expression via rAAV2 was mostly limited to one hemisphere. rAAV1, however, induced apoptosis and microglial activation but rAAV5 did not. Therefore, rAAV5 was selected for therapeutic scFv59 delivery in TgAβPPswe/PS1dE9 mice. rAAV5 was similarly injected into the ventricle of 10-month-old TgAβPPswe/PS1dE9 mice and 5 months later its efficacy and safety were evaluated. Immunoreactive Aβ deposits reduced in the hippocampus. Aβ42 levels in cerebrospinal fluid (CSF) tended to increase and the Aβ40 : 42 ratio decreased in CSF, suggesting that Aβ42 was relocated from the parenchyma to CSF. Hemorrhages associated with a focal increase in blood vessel amyloid were found in the brain. While immunotherapy has great potential for clearing cerebral Aβ, caution for cerebrovascular effects should be exercised when rAAV-mediated anti-Aβ immunotherapy is applied. Show more

Keywords: Adeno-associated virus, Alzheimer's disease, amyloid, cerebral hemorrhage, immunotherapy, single-chain antibodies

DOI: 10.3233/JAD-2011-110230

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 23-38, 2011

Authors: Pérès, Karine | Helmer, Catherine | Amieva, Hélène | Matharan, Fanny | Carcaillon, Laure | Jacqmin-Gadda, Hélène | Auriacombe, Sophie | Orgogozo, Jean-Marc | Barberger-Gateau, Pascale | Dartigues, Jean-François

Article Type: Research Article

Abstract: Subjective memory complaint (SMC) and restriction in cognitively-complex activities of daily living (such as instrumental ADL) are two early symptoms observed in the prodromal phase of dementia and may represent useful alarm signals for general practitioners for an increased risk of subsequent dementia. We here studied in a large population-based epidemiological cohort on aging, the risk of dementia associated with SMC and restriction in IADL, with a specific interest in a potential interaction by gender. The sample included 2,901 subjects, aged 65 years and over, initially free of dementia and followed over 15 years. After controlling for education, marital status, …depressive symptomatology, and global cognition (MMSE), IADL-restriction was associated with an increased risk of dementia only in men (HR = 2.04, 1.27 to 3.29), whereas SMC was not (p = 0.95). The reverse was observed in females, in whom SMC almost doubled the risk of dementia (1.48 to 2.41), with no association with IADL-restriction (p = 0.74). Finally, we distinguished the risk of dementia at short-term (in the first 5 years), mid-term (between 5 and 10 years), and long-term (between 10 and 15 years). In women, SMC was significantly associated with greater risk of dementia whatever the risk period considered, even at longer term (HR = 1.61, p = 0.0216), whereas in men the increased risk was also observed with IADL-restriction and only in the first 5 years. To conclude, women would report the first symptoms very early in the process by SMC, whereas men would tend to later report their difficulties and only in terms of IADL-restriction. Show more

Keywords: Activities of daily living, aged, cohort studies, dementia, memory disorders

DOI: 10.3233/JAD-2011-110428

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 39-47, 2011

Authors: Davies, Sean S. | Bodine, Chris | Matafonova, Elena | Pantazides, Brooke G. | Bernoud-Hubac, Nathalie | Harrison, Fiona E. | Olson, Sandra J. | Montine, Thomas J. | Amarnath, Venkataraman | Roberts II, L. Jackson

Article Type: Research Article

Abstract: Both inflammation and oxidative injury are features of Alzheimer's disease (AD), but the contribution of these intertwined phenomena to the loss of working memory in this disease is unclear. We tested the hypothesis that highly reactive γ-ketoaldehydes that are formed both by non-enzymatic free radical catalyzed lipid peroxidation and by cyclooxygenases may be causally linked to the development of memory impairment in AD. We found that levels of γ-ketoaldehyde protein adducts were increased in the hippocampus of brains obtained postmortem from patients with AD compared to age-matched controls, but that levels of γ-ketoaldehyde protein adducts in the cerebellum were not …different in the two groups. Moreover, immunohistochemistry revealed that adducts localized to hippocampal pyramidal neurons. We tested the effect of an orally available γ-ketoaldehyde scavenger, salicylamine, on the development of spatial working memory deficits in hApoE4 targeted replacement mice, a mouse model of dementia. Long-term salicylamine supplementation did not significantly alter body weight or survival, but protected against the development of age-related deficits in spatial working memory in 12–14 month old ApoE4 mice. These findings suggest that γ-ketoaldehyde adduct formation is associated with damage to hippocampal neurons in patients with AD and can contribute to the pathogenesis of spatial working memory deficits in hApoE4 mice. These data provide a rational basis for future studies exploring whether γ-ketoaldehyde scavengers may mitigate the development of cognitive dysfunction in patients with AD. Show more

Keywords: Aldehydes, Alzheimer's disease, inflammation, isolevuglandin, oxidative stress, salicylamine, working memory

DOI: 10.3233/JAD-2011-102118

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 49-59, 2011

Authors: Viana, Ricardo J.S. | Steer, Clifford J. | Rodrigues, Cecília M.P.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide-induced neurotoxicity is typically associated with cell death through mechanisms not entirely understood. Here, we investigated stress signaling events triggered by soluble Aβ in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ induced nuclear fragmentation that was prevented by pre-treatment with the antiapoptotic bile acid tauroursodeoxycholic acid (TUDCA). In addition, Aβ exposure triggered an early signaling response by the endoplasmic reticulum (ER) and caspase-12-mediated apoptosis, which, however, was independent of the ER-stress pathway. Furthermore, ER stress markers, including GRP94, ATF-6α, CHOP, and eIF2α, were strongly downregulated by Aβ, independent of protein degradation, and partially …restored by TUDCA. Calpain inhibition prevented caspase-12 activation and reduced levels of ATF-6α. Importantly, Aβ-induced GRP94 downregulation was related to protein secretion and partially rescued through inhibition of the secretory pathway by geldanamycin and brefeldin. In conclusion, we showed that the ER is a proximal stress sensor for soluble Aβ-induced toxicity, resulting in caspase-12 activation and cell death in PC12 neuronal cells. Moreover, ER chaperone GRP94 secretion was associated with Aβ-induced apoptotic signaling. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway is likely to provide new perspectives for modulation of amyloid-induced apoptosis. Show more

Keywords: Amyloid-β, ATF-6α, caspase-12, endoplasmic reticulum, GRP94, tauroursodeoxycholic acid

DOI: 10.3233/JAD-2011-100395

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 61-73, 2011

Authors: Alikhani, Nyosha | Guo, Lan | Yan, Shiqiang | Du, Heng | Pinho, Catarina Moreira | Chen, John Xi | Glaser, Elzbieta | Yan, Shirley ShiDu

Article Type: Research Article

Abstract: Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. …We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD. Show more

Keywords: Mitochondrial amyloid-β, mitochondrial function, oxidative stress, presequence protease (PreP), proteolysis

DOI: 10.3233/JAD-2011-101716

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 75-87, 2011

Authors: Yin, Jun-xiang | Turner, Gregory H. | Lin, Hao-jie | Coons, Stephen W. | Shi, Jiong

Article Type: Research Article

Abstract: Apolipoprotein E ε4 (ApoE4) has been implicated as a potential genetic risk factor for dementia. In this study, we investigate the effect of ApoE4 on learning and memory, changes in brain volume and neuroinflammatory responses in brain of ApoE4 transgenic mice. Four groups of male mice with ApoE4 and age-matched wild type (WT) (6-, 12-, 18- and 24-month) were studied. Spatial learning and retaining of mice was examined in the Morris Water Maze (MWM). Changes in brain volume (including the whole brain, hippocampus, cortex, total ventricles, and caudate putamen) were assessed by using 7T small animal MRI. Neuroinflammatory responses were …analyzed by measuring the levels of microglia (Iba-1), iNOS, TNFα, and IL-6 quantitatively. In the MWM, ApoE4 mice showed longer escape latency (p < 0.05) and swim distance (p < 0.05) at age 12 month and older, comparing with the WT mice. They also demonstrated poor memory retention in the probe test (p < 0.05). Brain atrophy was significant in ApoE4 mice than age-matched WT mice (18 months: 0.079 ± 0.004 versus 0.086 ± 0.003, p = 0.018; and 24 months: 0.074 ± 0.005 versus 0.084 ± 0.006, p = 0.008). The expression of Iba-1, iNOS, and TNFα in hippocampus and cortex were significantly higher in ApoE4 mice than in WT mice at 12 months and older. These data suggest that ApoE4 plays an important role in learning and memory impairment. These deficits are associated with neuroinflammatory responses that may in turn lead to atrophy in hippocampus and cortex. Show more

Keywords: Aging, apolipoprotein E, cognition, hippocampus

DOI: 10.3233/JAD-2011-110479

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 89-98, 2011

Authors: Fisher, Yair | Nemirovsky, Anna | Baron, Rona | Monsonego, Alon

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in the brain is one of the hallmarks of Alzheimer's disease (AD). T-cell entry into vascular and parenchymal brain areas loaded with Aβ has been observed with both beneficial as well as detrimental effects. Using a new AD mouse model, we studied the molecular mechanisms allowing CD4 T cells to specifically target Aβ-loaded brain areas. We observed that following Aβ immunization, CD11c+ dendritic cells (DCs) and CD4 T cells occurred primarily in the perivascular and leptomeningial spaces of cerebral vessels deposited with Aβ. CD11c+ cells expressed high levels of the DC maturation markers DEC-205, MHC …class II and CD86. Notably, the majority of cerebral blood vessels were found adjacent to Aβ plaques, expressing high levels of the ICAM-1 and VCAM-1 adhesion molecules. We propose that the drainage of Aβ to the leptomeningeal and perivascular spaces and its deposition there provide the antigenic source for DCs to stimulate Aβ-specific T cells on their way to target amyloid plaques within the brain tissue. Show more

Keywords: Alzheimer's disease, amyloid-β, dendritic cells, T cells

DOI: 10.3233/JAD-2011-102034

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 99-111, 2011

Authors: Yang, Hongqian | Lyutvinskiy, Yaroslav | Soininen, Hilkka | Zubarev, Roman A.

Article Type: Research Article

Abstract: Increased levels of isoaspartyl residues (isoAsp) have previously been found in proteins of Alzheimer's disease (AD) brains and in blood proteins of patients suffering from uremia, the disease sharing common pathological features with AD. One can hypothesize that higher levels of isoAsp should be present in blood proteins of AD patients. Also, because of higher AD prevalence in females, they can be expected to have higher level of isoAsp than males. Here we modified our recently developed proteome-wide isoAsp analysis approach for testing these hypotheses. Eight blood plasma samples pooled from 218 individuals suffering from either mild cognitive impairment (MCI) …or AD were analyzed by tandem mass spectrometry using electron transfer dissociation. Based on specific fragmentation pattern of isoAsp, the healthy controls were found to contain lower level of isoAsp compared with age-matched MCI and AD patients (p = 0.03). This result was further validated (p = 0.05) by 96 individual sample analyses, giving the combined value of p ≈ 0.01. Female pooled samples were found to contain higher level of isoAsp than male in both pooled and individual samples, with overall p ≈ 0.01. These findings verify the above hypotheses, and provide protein candidates for further investigation of the link between isoAsp and AD. Show more

Keywords: Aspartyl isomerization, blood plasma, electron capture dissociation, label-free quantification, tandem mass spectrometry

DOI: 10.3233/JAD-2011-110626

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 113-118, 2011

Authors: Maetzler, Walter | Stapf, Anne Kathrin | Schulte, Claudia | Hauser, Ann-Kathrin | Lerche, Stefanie | Wurster, Isabel | Schleicher, Erwin | Melms, Arthur | Berg, Daniela

Article Type: Research Article

Abstract: Recent studies have provided evidence that uric acid (UA), a natural antioxidant, may play a role in the development and progression of Parkinson's disease (PD) and of dementia. In this clinical study we were therefore interested in the role of UA in Lewy body disorders (LBD), which includes Parkinson's disease (PD) and a common form of neurodegenerative dementias, dementia with Lewy bodies (DLB). Ninety-five LBD patients (55 non-demented PD patients, PDND; 20 PD patients with dementia, PDD; and 20 DLB patients) and 76 controls underwent clinical and biochemical analyses including, from a subcohort, cerebrospinal fluid (CSF) analyses, and analysis of …three single nucleotide polymorphisms (SNPs) known to be associated with altered serum UA levels. We confirmed previous findings of lowered serum UA levels in LBD patients compared to controls. In CSF, UA levels were significantly higher in PDND patients (median 0.7 mg/dl) compared only to demented LBD patients (0.4 mg/dl; p = 0.03), but not to controls (0.5 mg/dl; p = 0.12). CSF UA levels correlated positively with CSF Aβ42 levels. This correlation was highest in controls (ρ = 0.67), intermediate in PDND (ρ = 0.49), but not observable in demented LBD patients (ρ = 0.10). These findings suggest an involvement of serum UA in LBD occurrence, and an involvement of CSF UA in cognitive decline in LBD, possibly through the Aβ pathway. SNP rs1165205 (SLC17A3) was weakly associated with altered CSF UA levels. Taken together, our results provide first evidence for disease-relevant but potentially distinct roles of UA in the blood and CSF compartment, respectively, in LBD. Show more

Keywords: Amyloid-β, oxidative stress, Parkinson's disease, single nucleotide polymorphism, uric acid

DOI: 10.3233/JAD-2011-110587

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 119-126, 2011

Authors: Choi, Im Seop | Lee, Young-Jung | Choi, Dong-Young | Lee, Yong Kyung | Lee, Yeun Hee | Kim, Ki Ho | Kim, Young Heui | Jeon, Young Ho | Kim, Eun Hee | Han, Sang Bae | Jung, Jae Kyung | Yun, Yeo Pyo | Oh, Ki-Wan | Hwang, Dae Youn | Hong, Jin Tae

Article Type: Research Article

Abstract: Accumulations of amyloid-β (Aβ) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in Aβ-injected and presenilin 2 mutant mice through the reduction of accumulated Aβ. To investigate mechanisms of the reduced Aβ accumulation, we examined generation, degradation, efflux and aggregation of Aβ in Swedish AβPP AD model (AβPPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of Aβ1-42 accumulation …in the brains of AβPPsw mice. According to the reduction of Aβ1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AβPP cleaving enzyme (BACE1), but increased clearance of Aβ in the brain through an increase of expressions and activities of Aβ degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of Aβ transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O-methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of AβPPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the AβPPsw mousee brain through inactivation of caspase-3 and BAX. These results suggest that 4-O-methylhonokiol might prevent the development and progression of AD by reducing Aβ accumulation through an increase of clearance and decrease of Aβ generation via antioxidant mechanisms. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPPsw mouse, 4-O-methylhonokiol, oxidative stress

DOI: 10.3233/JAD-2011-110545

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 127-141, 2011

Authors: Cornejo, Alberto | Jiménez, José M. | Caballero, Leonardo | Melo, Francisco | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-β) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical …properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products. Show more

Keywords: Alzheimer's disease, atomic force microscopy, disassembly, fulvic acid, tau aggregation

DOI: 10.3233/JAD-2011-110623

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 143-153, 2011

Authors: David, Renaud | Friedman, Leah | Mulin, Emmanuel | Noda, Art | Le Duff, Franck | Kennedy, Quinn | Garcia, Rene | Robert, Philippe H. | Yesavage, Jerome A. | Zeitzer, Jamie M. | and for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in catechol-O-methyltransferase (COMT) are associated with apathy in individuals with Alzheimer's disease (AD). We analyzed a cohort of 105 Caucasian individuals with AD (age = 79.3 ± 7.03 years; MMSE = 20.2 ± 4.4) according to the presence of apathy, as defined either by the Neuropsychiatric Inventory or the Apathy Inventory. Polymorphisms in seventeen SNPs in COMT were examined. A replication cohort consisting of 176 Caucasian AD subjects in the ADNI database was also analyzed. None of the candidate gene SNPs were significantly associated with the presence of apathy in either …cohort. We did not find any SNPs in COMT that were consistently associated with apathy in individuals with AD. Show more

Keywords: Alzheimer's disease, apathy, catechol-O-methyltransferase, dopamine, single nucleotide polymorphisms

DOI: 10.3233/JAD-2011-110491

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 155-161, 2011

Authors: Mattila, Jussi | Koikkalainen, Juha | Virkki, Arho | Simonsen, Anja | van Gils, Mark | Waldemar, Gunhild | Soininen, Hilkka | Lötjönen, Jyrki | and for The Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Diagnostic processes of Alzheimer's disease (AD) are evolving. Knowledge about disease-specific biomarkers is constantly increasing and larger volumes of data are being measured from patients. To gain additional benefits from the collected data, a novel statistical modeling and data visualization system is proposed for supporting clinical diagnosis of AD. The proposed system computes an evidence-based estimate of a patient's AD state by comparing his or her heterogeneous neuropsychological, clinical, and biomarker data to previously diagnosed cases. The AD state in this context denotes a patient's degree of similarity to previously diagnosed disease population. A summary of patient data and results …of the computation are displayed in a succinct Disease State Fingerprint (DSF) visualization. The visualization clearly discloses how patient data contributes to the AD state, facilitating rapid interpretation of the information. To model the AD state from complex and heterogeneous patient data, a statistical Disease State Index (DSI) method underlying the DSF has been developed. Using baseline data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the ability of the DSI to model disease progression from elderly healthy controls to AD and its ability to predict conversion from mild cognitive impairment (MCI) to AD were assessed. It was found that the DSI provides well-behaving AD state estimates, corresponding well with the actual diagnoses. For predicting conversion from MCI to AD, the DSI attains performance similar to state-of-the-art reference classifiers. The results suggest that the DSF establishes an effective decision support and data visualization framework for improving AD diagnostics, allowing clinicians to rapidly analyze large quantities of diverse patient data. Show more

Keywords: Alzheimer's disease, automatic, biomarkers, computer-assisted, decision making, information processing, projections and predictions

DOI: 10.3233/JAD-2011-110365

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 163-176, 2011

Authors: Correia, Clarice Câmara | Lima, Fábia | Junqueira, Franco | Campos, Marília Siqueira | Bastos, Othon | Petribú, Kátia | Laks, Jerson | Galvin, James E

Article Type: Research Article

Abstract: Dementia is a global public health problem and detection in the primary care setting, particularly in developing countries, is challenging. The aim of this research was to produce the cross-cultural validation of the AD8 interview to the Brazilian Portuguese Language. The original version of the AD8 was submitted to translation, back-translation, and application of the questionnaire to 20 elderly informants for face validation. The AD8-Brazil was then evaluated in 109 community-dwelling elderly with a sociodemographic questionnaire, clinical examination, Mini Mental State Examination (MMSE), Katz Inventory of Activities of Daily Living (ADL), and Clinical Dementia Rating scale (CDR). The AD8-Brazil was …compared with the other instruments and with the clinical diagnosis (DSM-IV) for criterion validation. There was significant agreement of AD8-Brazil with diagnosis of dementia (p < 0.001), MMSE (p = 0.047), and ADL (PFisher = 0.004). Also, the AD8-Brazil was able to differentiate the stages of dementia by CDR scale. The reliability was high (alpha = 0.818) and reproducibility analysis showed excellent inter-rater (kappa = 0.889) and test-retest consistency (kappa = 0.814). The AD8-Brazil showed excellent discrimination between CDR 0 and CDR > 0 (area under the curve 86.1%) and between CDR 0 and CDR 0.5 (area under the curve 76.9%). The administration of the questionnaire took 2.3 ± 0.1 minutes. The Brazilian version of the AD8 is a valid, reliable, quick, and easy screening instrument for dementia. Show more

Keywords: AD8, cross-cultural, dementia, elderly, screening

DOI: 10.3233/JAD-2011-100915

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 177-185, 2011

Authors: Luengo-Fernandez, Ramon | Leal, Jose | Gray, Alastair M.

Article Type: Research Article

Abstract: Dementia has a significant impact on the health and social care systems of the European Union (EU), on patients, on family and friends who provide unpaid care, and on the wider economy and society. Information about its economic burden will be helpful when deciding the allocation of future research funds. We included the 15 countries who were members of the EU (EU-15) before the Eastern enlargement in 2004. The economic burden of dementia was estimated using patient-level studies and aggregate data on morbidity, mortality, and health and social care use. The same methodological approach was used across all countries. Healthcare …and social care costs were estimated from expenditure on nursing and residential home care; and primary, outpatient, emergency and inpatient care, as well as drug treatment. Costs of unpaid care and lost earnings due to morbidity and premature death were also included in the study. Dementia was estimated to cost the EU-15 €189 billion in 2007. 68% of total costs were due to informal care, 26% to social care, 5% to health care and 1% to productivity losses. In conclusion, dementia poses a significant economic burden to European health and social care systems, and society overall. Our results will be helpful for policy makers in evaluating policy impact and prioritising research expenditures. This study also highlights the need for more accurate and comparable dementia-related data across the European countries. Show more

Keywords: Alzheimer's disease, cost of illness, dementia, research

DOI: 10.3233/JAD-2011-102019

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 187-196, 2011

Authors: Maruszak, Aleksandra | Safranow, Krzysztof | Branicki, Wojciech | Gawęda-Walerych, Katarzyna | Pośpiech, Ewelina | Gabryelewicz, Tomasz | Canter, Jeffrey A. | Barcikowska, Maria | Żekanowski, Cezary

Article Type: Research Article

Abstract: We investigated the potential contribution of mitochondrial DNA (mtDNA) variants, haplogroups, and polymorphisms in nuclear genes essential for mitochondrial biogenesis and function (PGC-1α TFAM) to late-onset Alzheimer's disease (LOAD) risk. Epistatic interaction analysis was conducted between the studied variables. Our results demonstrate that mtDNA haplogroups and subhaplogroups with putative role in partial uncoupling of oxidative phosphorylation are significantly associated with a decreased LOAD risk (OR <1). Conversely, mtDNA haplogroup H (p = 0.049) and HV cluster (p = 0.018) are significant LOAD risk factors, which was additionally confirmed by meta-analysis (OR = 1.22, OR = 1.25, respectively). Haplogroup K was …demonstrated to exert a neutralizing effect on the high risk associated with APOE4+ status (p = 0.014). Further, two synergistic interactions between subhaplogroup H5 and APOE4 status (p = 0.009) and between TFAM rs1937 and APOE4 status (p < 0.001) were detected, influencing LOAD risk. No interaction pointing to a dual mitochondrial-nuclear genome variation effect on LOAD occurrence was identified. Show more

Keywords: Alzheimer's disease, control region, mitochondrial DNA, mitochondrial haplogroups, polymorphism

DOI: 10.3233/JAD-2011-110710

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 197-210, 2011

Authors: Dumont, Magali | Kipiani, Khatuna | Yu, Fangmin | Wille, Elizabeth | Katz, Maya | Calingasan, Noel Y. | Gouras, Gunnar K. | Lin, Michael T. | Beal, M. Flint

Article Type: Research Article

Abstract: Increased oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD). A large body of evidence suggests that mitochondrial dysfunction and increased reactive oxygen species occur prior to amyloid-β (Aβ) deposition. Coenzyme Q10 (CoQ10), a component of the mitochondrial electron transport chain, is well characterized as a neuroprotective antioxidant in animal models and human trials of Huntington's disease and Parkinson's disease, and reduces plaque burden in AβPP/PS1 mice. We now show that CoQ10 reduces oxidative stress and amyloid pathology and improves behavioral performance in the Tg19959 mouse model of AD. CoQ10 treatment decreased brain levels of protein carbonyls, a …marker of oxidative stress. CoQ10 treatment resulted in decreased plaque area and number in hippocampus and in overlying cortex immunostained with an Aβ42 -specific antibody. Brain Aβ42 levels were also decreased by CoQ10 supplementation. Levels of amyloid-β protein precursor (AβPP) β-carboxyterminal fragments were decreased. Importantly, CoQ10-treated mice showed improved cognitive performance during Morris water maze testing. Our results show decreased pathology and improved behavior in transgenic AD mice treated with the naturally occurring antioxidant compound CoQ10. CoQ10 is well tolerated in humans and may be promising for therapeutic trials in AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein, coenzyme Q10, cognition, oxidative stress

DOI: 10.3233/JAD-2011-110209

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 211-223, 2011

Authors: Ma, Linqing | Ohyagi, Yasumasa | Nakamura, Norimichi | Iinuma, Kyoko M. | Miyoshi, Katsue | Himeno, Eri | Soejima, Naoko | Yanagihara, Yuki T. | Sakae, Nobutaka | Yamasaki, Ryo | Kira, Jun-ichi

Article Type: Research Article

Abstract: Apomorphine hydrochloride (APO) is known to be a dopamine receptor agonist, and has recently been found to be a novel drug for Alzheimer's disease (AD). We found that APO treatment ameliorated oxidative stress in an AD mouse model and specifically attenuated the hydrogen peroxide-induced p53-related apoptosis in the SH-SY5Y neuroblastoma cell line. To further understand the mechanism behind this action, we investigated the actions of APO on intracellular redox systems, such as the glutathione cycle and catalase. We studied the effects of specific inhibitors for glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (BCNU, MCS, and ATZ, respectively) on the …effects of APO. Treatments with MCS or BCNU, but not ATZ, significantly attenuated the protective effects of APO. Interestingly, APO treatment elevated GPx activity, but did not increase the expression of the GPx1 protein. Although BCNU treatment attenuated APO effects, GR activity was not elevated by APO treatment. The same effects were observed in primary neuronal cultures. In addition, treatment with dopamine D1, D2, D3 and D4 receptor antagonists did not counteract the protective action of APO. Thus, APO may enhance GPx activity through dopamine receptor-independent pathways. Show more

Keywords: Apomorphine, catalase, glutathione peroxidase, glutathione reductase, oxidative stress, p53

DOI: 10.3233/JAD-2011-110140

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 225-237, 2011

Article Type: Correction

Abstract: Erratum to [Journal of Alzheimer's Disease 24(4), 2011, 775–783], DOI 10.3233/JAD-2011-101371]

DOI: 10.3233/JAD-2011-1441

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 239-239, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110909

Citation: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 241-242, 2011