Journal of Alzheimer's Disease - Volume 26, issue 1

Authors: Whitehouse, Peter J. | George, Daniel R.

Article Type: Editorial

DOI: 10.3233/JAD-2011-111020

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 1-5, 2011

Authors: Murakami, Kazuma | Murata, Nakaba | Ozawa, Yusuke | Kinoshita, Noriaki | Irie, Kazuhiro | Shirasawa, Takuji | Shimizu, Takahiko

Article Type: Research Article

Abstract: Oxidative stress is related to the pathogenesis of Alzheimer's disease (AD) characterized by progressive memory impairment. Soluble amyloid-β (Aβ) oligomers cause cognitive loss and synaptic dysfunction rather than senile plaques in AD. The decline of the antioxidant status is associated with dementia in AD patients, especially low levels of vitamin C. Our group previously reported a relationship between anti-aging and supplementation of vitamin C derivatives. Here we report that vitamin C mitigated Aβ oligomer formation and behavioral decline in an AD mouse model treated with a vitamin C solution for 6 months. The attenuation of Aβ oligomerization was accompanied with …a marked decrease in brain oxidative damage and in the ratio of soluble Aβ42 to Aβ40 , a typical indicator of AD progression. Furthermore, the intake of vitamin C restored the declined synaptophysin and the phosphorylation of tau at Ser396. On the other hand, brain plaque deposition was not altered by the dietary intake of vitamin C. These results support that vitamin C is a useful functional nutrient for the prevention of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, anxiety, hyperactivity, oligomer, vitamin C

DOI: 10.3233/JAD-2011-101971

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 7-18, 2011

Authors: Villa, Chiara | Ghezzi, Laura | Pietroboni, Anna M. | Fenoglio, Chiara | Cortini, Francesca | Serpente, Maria | Cantoni, Claudia | Ridolfi, Elisa | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Jacini, Francesca | Arighi, Andrea | Fumagalli, Giorgio G. | Mandelli, Alessandra | Binetti, Giuliano | Cappa, Stefano | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: A number of mutations in microtubule associated protein tau gene (MAPT), causing frontotemporal lobar degeneration (FTLD) with tau pathology, are located in the four-repeated microtubule (MT) binding domains and affect the ability of tau to bind MTs. Here, we describe a novel variant lying in the second MT domain, found in a female patient diagnosed clinically with progressive nonfluent aphasia (PNFA), with a positive family history for dementia. At 65 years, she started developing progressive language deficits, characterized by expression difficulties and word coordination impairment. She came to our attention at 67 years. Her MMSE score was 22/30. A Brain …CT scan showed mild diffuse cortical atrophy, ventricles' asymmetry (left > right), and very mild signs of chronic vasculopathy. Cerebrospinal fluid analysis showed normal amyloid-β42 , tau, and P-tau levels. She was diagnosed with PNFA according to current diagnostic criteria. A novel exon 10 MAPT variant was identified (g.123798G > A), which leads to an amino acidic change (p.Gly304Ser) in the second MT microtubule binding domain. In silico analysis predicted that this variant is damaging on protein structure and function. Additional 168 FTLD patients and 503 controls screened (1342 chromosomes) did not carry the variant, suggesting that it is a mutation rather than a polymorphism. The amino acid change likely compromises the ability of tau to properly regulate the dynamic behavior of microtubules. Show more

Keywords: frontotemporal lobar degeneration (FTLD), MAPT, mutation, phenotype, progressive nonfluent aphasia (PNFA)

DOI: 10.3233/JAD-2011-102124

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 19-26, 2011

Authors: Lenoir, Hermine | Dufouil, Carole | Auriacombe, Sophie | Lacombe, Jean-Marc | Dartigues, Jean-François | Ritchie, Karen | Tzourio, Christophe

Article Type: Research Article

Abstract: The aim of our study was to investigate whether depression assessed by different markers predicts the risk of incident dementia in elderly individuals. Data was derived from the 3C cohort study conducted in community-dwelling individuals aged 65 years and over, randomly recruited from electoral rolls of three French areas and followed up for four years (1999–2001 through 2004) with assessments every 2 years. The study sample comprised 7989 dementia-free individuals (mean age, 74.0 years; 61% women) assessed at baseline for current or past Major Depressive Episodes (MDE) based on MDE module of the Mini International Neuropsychiatric Interview, self-reported lifetime treated …depression, and level of depressive symptoms using the Center for Epidemiologic Studies-Depression Scale. Fully adjusted Cox proportional hazards models were applied to examine the risk of incident dementia associated with these markers of depression. MDE and self-reported lifetime treated depression did not increase incident dementia risk. Conversely, high level of depressive symptoms at baseline was associated with a 50% increased risk of dementia (adjusted Hazard Ratio [HR], 1.5; 95% Confidence interval [CI], 1.2–2.2). This result was driven by a five-fold increased risk of vascular dementia (HR, 4.8; 95% CI, 2.2–10.7; p < 0.0001), whereas there was no increased risk of Alzheimer's disease (1.0; 0.7–1.6). In elderly individuals, high level of depressive symptoms is predictive of vascular dementia within a few years. This close temporal association suggests that depression is less a risk factor for than a prodromal symptom of vascular dementia. Show more

Keywords: Cohort studies, dementia, depression, elderly, risk factors

DOI: 10.3233/JAD-2011-101614

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 27-38, 2011

Authors: Laske, Christoph | Sopova, Kateryna | Hoffmann, Nadine | Stransky, Elke | Hagen, Katja | Fallgatter, Andreas J. | Stellos, Konstantinos | Leyhe, Thomas

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of Mini-Mental State Examination …[MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive decline (decrease of MMSE score ≤ 4 after one year; n = 28) (fast versus slow cognitive decline: mean ± SD: 1051.1 ± 178.7 versus 1237.9 ± 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels, as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lower SCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis. Show more

Keywords: Alzheimer's disease, cognitive decline, hematopoietic growth factors, stem cell factor

DOI: 10.3233/JAD-2011-110008

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 39-45, 2011

Authors: Gao, Junling | Cheung, Raymond Tak-Fai | Lee, Tatia M.C. | Chu, Leung-Wing | Chan, Ying-Shing | Mak, Henry Ka-Fung | Zhang, John X. | Qiu, Deqiang | Fung, Germaine | Cheung, Charlton

Article Type: Research Article

Abstract: Retrogenesis refers to the phenomenon by which degenerative processes in aging reverse the sequence of acquisition in development. Although there has been some evidence for brain retrogenesis in abnormal aging, e.g., Alzheimer's disease (AD), it has not been explicitly addressed in the normal aging. Using diffusion tensor imaging and tractography, we explored the effects of normal and abnormal aging on the integrity of white matter (WM) in fifty participants, including 18 AD patients, 17 normal elderly, and 15 normal young adults. Compared with young adults, the traditional voxel-based analysis, and the quantitative fiber tracking methods revealed lower fractional anisotrophy (FA) …for both normal elderly and AD patients, indicating WM disintegrity in the anterior part of the brain with developmentally late-myelinating fiber bundles. Furthermore, AD patients showed lower FA in the posterior part of the brain with relatively early-myelinating fiber bundles. Additional analysis on axial diffusion and radial diffusion measures suggest that demyelination may be the main mechanism underlying the observed microstructural impairments. Consistent with a proposal of retrogenesis, our results demonstrate an anteroposterior pattern of white matter disintegrity in both normal aging and AD, with the pattern being more salient in the latter than in the former. Show more

Keywords: Aging, Alzheimer's disease, diffusion tensor imaging, fiber tracking, retrogenesis, white matter integrity

DOI: 10.3233/JAD-2011-101788

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 47-58, 2011

Authors: Torres, Larissa Lobo | Quaglio, Nathalia Barbosa | de Souza, Gisele Tavares | Garcia, Raphael Tamborelli | Dati, Lívia Mendonça Munhoz | Moreira, Wallace Luiz | de Melo Loureiro, Ana Paula | de souza-Talarico, Juliana Nery | Smid, Jerusa | Porto, Cláudia Selito | de Campos Bottino, Cássio Machado | Nitrini, Ricardo | de Moraes Barros, Silvia Berlanga | Camarini, Rosana | Marcourakis, Tania

Article Type: Research Article

Abstract: Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative …stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = −0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = −0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders. Show more

Keywords: Aging, Alzheimer's disease, antioxidant enzymes, malonaldehyde, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2011-110284

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 59-68, 2011

Authors: Bach, Jan-Philipp | Mengel, David | Wahle, Tina | Kautz, Andreas | Balzer-Geldsetzer, Monika | Al-Abed, Yousef | Dodel, Richard | Bacher, Michael

Article Type: Research Article

Abstract: Amyloid-β (Aβ) oligomer toxicity is a crucial factor in the development of Alzheimer's disease. Therefore, the aim of therapeutic research is to target the modification of secretase activity, increase Aβ degradation, reduce Aβ formation, and modulate Aβ-induced neuroinflammation. Recently, the p38 MAP kinase inhibitor CNI-1493 has been shown to reduce plaque load and has led to an improvement in memory performance in a transgenic mouse model. We examined the role of CNI-1493 in the microglial inflammatory response to Aβ using both a microglia cell line as well as primary microglia isolated from mesocortices. MTT assays were performed to quantify cell …viability. FACS analysis was used to measure phagocytosis. We used ELISA to analyse cytokine concentrations in response to CNI-1493 treatment. Western-blot/Dot-blot techniques were used to show the interaction of CNI-1493 with Aβ-oligomers as well as to measure apoptosis in microglia cells. RT-PCR was used to analyze secretase expression, and secretase function was determined using fluorimetric assays. CNI-1493 is able to prevent oligomer formation as well as apoptosis in microglia. A significant reduction was found in the Aβ-induced release of IL-6 and TNF-α in the presence of CNI-1493. Phagocytosis is an essential Aβ removal mechanism and was enhanced by CNI-1493 in primary microglia. CNI-1493 also influenced the α-secretase product C83 with an increase in the treated cells, while a simultaneous reduction in Aβ secretion was also observed. We hypothesize that CNI-1493 not only reduces neuroinflammation and consequent neurodegeneration, but also leads to a shift in AβPP-processing towards the non-amyloidogenic pathway. Therefore, CNI-1493 is a promising candidate for the treatment of AD. Show more

Keywords: α-secretase signaling, Alzheimer's disease, amyloid, inflammation, neurodegeneration

DOI: 10.3233/JAD-2011-110179

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 69-80, 2011

Authors: Loef, Martin | Schrauzer, Gerhard N. | Walach, Harald

Article Type: Research Article

Abstract: Preventing Alzheimer's disease (AD) would require knowledge about its etiology to a degree of detail not yet available. The major hurdle in understanding the disease lies in teasing out the various causes and their complex interactions. Since considerable data have accrued showing that the essential trace element selenium (Se) might play different roles in the progression of AD, we conducted a systematic review of the literature regarding Se and AD. We identified 9 placebo-controlled studies (6 were multiple supplement trials including Se, 1 was ongoing), 4 prospective, 4 cross-sectional, 15 case control, 24 autopsy studies, as well studies in animals …and cells. There is an absence of consistent clinical evidence as to whether supplementation of Se is beneficial in the treatment of AD and how Se levels are altered in brain, cerebrospinal fluid, and blood of patients with AD. Some longitudinal and cross-sectional studies, however, show an association of Se status and cognitive function. Findings from molecular biology reveal a decisive role of Se in the pathogenesis of AD. In summary, the current state of knowledge provides no evidence for a role of Se in the treatment of AD, but allows speculation on a potential preventive relevance. Large trials of long-term duration could provide definitive answers. Show more

Keywords: Alzheimer's disease, amyloid-β, dementia, NF-κB, oxidative stress, selenium, selenoproteins, systematic review trace elements, tau

DOI: 10.3233/JAD-2011-110414

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 81-104, 2011

Authors: Stewart, Sarah | Cacucci, Francesca | Lever, Colin

Article Type: Research Article

Abstract: We review studies testing performance on tasks putatively tapping spatial memory in the Tg2576 mouse model of Alzheimer's disease (AD). This model exhibits age-dependent elevation of amyloid-β in the hippocampal formation and elsewhere in the brain. From 49 articles in all, we reviewed Tg2576 performance on five spatial memory tasks: the reference memory version of the Morris water maze, continuous Y-maze alternation, discrete forced-choice T-maze alternation, the radial arm water maze, and the circular platform maze (Barnes maze). Proportionally, the likelihood of detecting significant impairment in Tg2576 mice (relative to age-matched controls) was found to be: highest with the use …of T-maze alternation and the radial arm water maze; intermediate when using the Morris water maze and continuous Y-maze alternation; and lowest when using the circular platform maze. These results are indicative rather than conclusive, but have implications for testing cognitive function in Tg2576 mice and, potentially, other AD rodent models. The apparent sensitivity of the T-maze alternation task and reduced sensitivity of the Morris water maze task (reference memory version) are discussed. We also consider limitations and potential improvements in assessing cognitive impairment in dementia models. Show more

Keywords: Alzheimer's disease, dementia, hippocampus, mouse model, reference memory, Tg2576, transgenic, working memory

DOI: 10.3233/JAD-2011-101827

Citation: Journal of Alzheimer's Disease, vol. 26, no. 1, pp. 105-126, 2011