Journal of Alzheimer's Disease - Volume 18, issue 1

Authors: Lebouvier, Thibaud | Scales, Timothy M.E. | Williamson, Ritchie | Noble, Wendy | Duyckaerts, Charles | Hanger, Diane P. | Reynolds, C. Hugh | Anderton, Brian H. | Derkinderen, Pascal

Article Type: Review Article

Abstract: Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease (AD), where it is hyperphosphorylated on serine and threonine residues. It is hypothesized that this hyperphosphorylation contributes to neurodegeneration through the destabilization of microtubules. There is now evidence that phosphorylation of tau can also occur on tyrosine residues. Human tau has five tyrosines numbered 18, 29, 197, 310, and 394, according to the sequence of the longest CNS isoform. Tyrosines 18, 197, and 394 have been shown to be phosphorylated in the brain of patients with AD whereas tyrosine 394 is the only residue that has …been described to date that is phosphorylated in physiological conditions. Src family kinases and spleen tyrosine kinase (Syk) have been shown to phosphorylate tyrosine 18 while c-Abl is capable of phosphorylating tyrosine 394. Recently, a dual specificity kinase termed TTBK1 has been characterized in human brain and shown to be able to phosphorylate residue 197 of tau. Data about the role of tau tyrosine phosphorylation in neuronal physiology are still scarce and preliminary. In contrast, there is mounting evidence suggesting that tau tyrosine phosphorylation is an early event in the pathophysiology of AD and that Fyn and c-Abl are critical in the neurodegenerative process which occurs in tauopathies. Show more

Keywords: Alzheimer's disease, c-Abl, Fyn, Lck, Src, Syk, tau, tauopathies, tyrosine phosphorylation

DOI: 10.3233/JAD-2009-1116

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 1-9, 2009

Authors: Monastero, Roberto | Mangialasche, Francesca | Camarda, Cecilia | Ercolani, Sara | Camarda, Rosolino

Article Type: Review Article

Abstract: Mild cognitive impairment (MCI) is a clinical concept proposed as an intermediate state between normal aging and dementia. This condition has multiple heterogeneous sources, including clinical presentation, etiology, and prognosis. Recently, the prevalence and associated features of neuropsychiatric symptoms (NPS) in MCI have been described. We systematically searched the PubMed database (last accessed on August 31, 2008) for articles on NPS in MCI. Included articles used strict selection criteria, and outcome variables were extracted in duplicate; of the 27 articles included, 14 (52%) used prospective cohorts. The global prevalence of NPS in MCI ranged from 35% to 85%. The most …common behavioral symptoms were depression, anxiety, and irritability. Hospital-based samples reported a higher global prevalence of NPS than population-based studies; this discrepancy probably reflected differences in demographics, study setting, MCI diagnostic criteria, and behavioral instruments used. Prospective studies showed that NPS, particularly depression, may represent risk factors for MCI or predictors for the conversion of MCI to Alzheimer's disease (AD). NPS are very prevalent in subjects with MCI, displaying a similar pattern of symptoms compared to dementia and AD. Large cohort studies using standardized MCI criteria and behavioral instruments are required to evaluate the prognostic role of NPS in MCI. Show more

Keywords: Alzheimer's disease, behavior, dementia, depression, incidence, mild cognitive impairment, neuropsychiatric symptoms, predictors, prevalence, risk factors

DOI: 10.3233/JAD-2009-1120

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 11-30, 2009

Authors: Dubey, Ashok K. | Bharadwaj, Prashant R. | Varghese, Joseph N. | Macreadie, Ian G.

Article Type: Short Communication

Abstract: Amyloid-β (Aβ42 ), which is known to be toxic to neuronal cells, protects yeast cells from severe sodium hydroxide toxicity. More than 85% cell death was caused by treatment with 1 mM NaOH and approximately 95% was observed at a 2 mM concentration. However, greater than 55% cells survived the treatment in the presence of Aβ42 . A strong protective effect of the peptide was also evident from the differential staining of the treated culture with propidium iodide.

Keywords: Alkali stress, amyloid-β protection, amyloid-β toxicity, peptide assay, yeast assay

DOI: 10.3233/JAD-2009-1121

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 31-33, 2009

Authors: Davis, Richard C. | Maloney, Michael T. | Minamide, Laurie S. | Flynn, Kevin C. | Stonebraker, Matthew A. | Bamburg, James R.

Article Type: Research Article

Abstract: Dissociated hippocampal neurons exposed to a variety of degenerative stimuli form neuritic cofilin-actin rods. Here we report on stimulus driven regional rod formation in organotypic hippocampal slices. Ultrastructural analysis of rods formed in slices demonstrates mitochondria and vesicles become entrapped within some rods. We developed a template for combining and mapping data from multiple slices, enabling statistical analysis for the identification of vulnerable sub-regions. Amyloid-β (Aβ) induces rods predominantly in the dentate gyrus region, and Aβ-induced rods are reversible following washout. Rods that persist 24 h following transient (30 min) ATP-depletion are broadly distributed, whereas rods formed in response to …excitotoxic glutamate localize within and nearby the pyramidal neurons. Time-lapse imaging of cofilin-GFP-expressing neurons within slices shows neuronal rod formation begins rapidly and peaks by 10 min of anoxia. In ∼50% of responding neurons, Aβ-induced rod formation acts via cdc42, an upstream regulator of cofilin. These new observations support a role for cofilin-actin rods in stress-induced disruption of cargo transport and synaptic function within hippocampal neurons and suggest both cdc42-dependent and independent pathways modulate cofilin activity downstream from Aβ. Show more

Keywords: Actin, actin depolymerizing factor (ADF)/cofilin, actin inclusions, Alzheimer's disease, amyloid-β, ischemic brain injury

DOI: 10.3233/JAD-2009-1122

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 35-50, 2009

Authors: Liu, Fan | Ikram, M. Arfan | Janssens, A. Cecile J.W. | Schuur, Maaike | de Koning, Inge | Isaacs, Aaron | Struchalin, Maksim | Uitterlinden, Andre G. | den Dunnen, Johan T. | Sleegers, Kristel | Bettens, Karolien | Van Broeckhoven, Christine | van Swieten, John | Hofman, Albert | Oostra, Ben A. | Aulchenko, Yurii S. | Breteler, Monique M. B. | van Duijn, Cornelia M.

Article Type: Research Article

Abstract: Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer's disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, …we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD. Show more

Keywords: Alzheimer's disease, association, cognitive function, SORL1

DOI: 10.3233/JAD-2009-1137

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 51-64, 2009

Authors: Aresi, Anna | Giovagnoli, Anna Rita

Article Type: Research Article

Abstract: This study investigated the neuropsychological hallmarks of posterior cortical atrophy (PCA). Seventeen patients with PCA, 17 patients with probable Alzheimer's disease (PAD), and 17 healthy age-matched subjects underwent neuropsychological testing for abstract reasoning, visuospatial abilities, memory, language, executive functions, praxes, and attention. The PCA patients were significantly more impaired in visual perception, spatial memory, visual attention, and visuospatial reasoning compared to the PAD patients who were relatively more impaired in episodic memory. In the PCA group, no test score correlated with disease duration or age of clinical onset, whereas, in the PAD group, several scores correlated with disease duration. Compared …to the healthy subjects, both patient groups showed multiple cognitive deficits. Thus, PCA is characterised by distinctive visuospatial deficits that reflect the distribution of brain damage and contrast with the memory impairment of PAD patients. Specific neuropsychological tests may contribute to early identification of cortical dementia for diagnostic and research purposes. Show more

Keywords: Alzheimer's disease, cognitive functions, dementia, memory, neuropsychological assessment, posterior cortical atrophy, progressive visual agnosia

DOI: 10.3233/JAD-2009-1123

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 65-70, 2009

Authors: Sundelöf, Johan | Kilander, Lena | Helmersson, Johanna | Larsson, Anders | Rönnemaa, Elina | Degerman-Gunnarsson, Malin | Sjögren, Per | Basun, Hans | Lannfelt, Lars | Basu, Samar

Article Type: Research Article

Abstract: Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer's disease (AD). In this study, serum α- and γ-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 616 and age 77, n = 761). In addition, urinary F2 -isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n = 679). Cox regression analyses were used to examine associations between serum α-, γ-tocopherol and urinary F2 -isoprostane levels and AD, any …type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum α- and γ-tocopherol or urinary F2 -isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum α- and γ-tocopherol and urinary F2 -isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia. Show more

Keywords: Alzheimer's disease, dementia, isoprostanes, oxidative stress, vitamins

DOI: 10.3233/JAD-2009-1125

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 71-78, 2009

Authors: Sundelöf, Johan | Kilander, Lena | Helmersson, Johanna | Larsson, Anders | Rönnemaa, Elina | Degerman-Gunnarsson, Malin | Basun, Hans | Lannfelt, Lars | Basu, Samar

Article Type: Research Article

Abstract: Inflammation is suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n = 1062 and age 77, n = 749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2α (PGF2α ) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, …hsCRP, SAA and PGF2α metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2α levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95% confidence interval 1.23–3.95, p-value = 0.008). A longitudinal change in CRP or IL-6 levels was not associated with AD or dementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2α levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia. Erratum in JAD20(2), p. 681. Show more

Keywords: Alzheimer's disease, biomarkers, dementia, inflammation

DOI: 10.3233/JAD-2009-1126

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 79-87, 2009

Authors: Zhou, Bin | Teramukai, Satoshi | Yoshimura, Kenichi | Fukushima, Masanori

Article Type: Research Article

Abstract: A systematic literature review was performed to assess the suitability of cerebrospinal fluid (CSF) levels of protein amyloid-β42 (Aβ42 ) and tau as markers to detect the disease-modifying effects of drugs in clinical trials of AD treatments. All databases were searched for observational studies, single-arm clinical trials, and randomized controlled trials involving patients with AD in which CSF Aβ42 and tau were measured. A meta-analytic random-effects model was used to evaluate the mean absolute change in protein concentration over time. Spearman correlation was used to assess the association between change in CSF protein concentration and change in cognitive …function. The mean changes per month in observational studies were −0.4 pg/ml/month (95% CI: −1.9 to 1.1) for 8 CSF Aβ42 and 1.5 pg/ml/month (95% CI: 0.1 to 3.0) for 12 CSF tau studies. The correlation coefficients for the relationship between CSF protein concentration and cognition were 0.43 (p = 0.068) for all 18 Aβ42 studies and −0.05 (p = 0.857) for all 18 tau studies. A trend in which CSF Aβ42 decreases and tau protein increases over time was identified in AD patients. CSF Aβ42 and tau concentrations should be used with caution as surrogate endpoints in early-phase clinical trials for AD. Show more

Keywords: Alzheimer's disease, amyloid-β42, biomarker, cerebrospinal fluid, tau

DOI: 10.3233/JAD-2009-1124

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 89-102, 2009

Authors: Quinn, Joseph | Clark, Christopher M.

Article Type: Article Commentary

DOI: 10.3233/JAD-2009-1128

Citation: Journal of Alzheimer's Disease, vol. 18, no. 1, pp. 103-104, 2009