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

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