Journal of Alzheimer's Disease - Volume 25, issue 4

Authors: D'Alton, Simon | George, Daniel R.

Article Type: Research Article

Abstract: The past two decades have seen an explosion in funding and research for Alzheimer's disease (AD), which has resulted in a wealth of data exploring the potential underlying processes, particularly with regard to amyloid-β (Aβ). However, to date, therapies based on this knowledge have not been forthcoming. In seeking an explanation for our current pharmacological failures, it has become clear that amyloid is only one part of a multi-factorial disease process incorporating a wealth of deleterious factors. Additionally, there is strong evidence that the initial production of Aβ is part of the evolutionarily conserved stress response, triggered by a host …of upstream factors highly altered in aging. Taken together, these observations place Aβ in a drastically different context, with toxicity occurring secondarily to upstream deleterious factors and rendering current therapeutic strategies oversimplified. This re-conceptualization necessitates a paradigm shift in our scientific and social response to AD, placing a greater emphasis on upstream interventions and public health awareness of the measures that can be taken by most individuals to reduce the risk of AD. With the increasing prevalence of AD and the realization that disease-modifying drugs may not be available in the near future, it is the responsibility of science to better communicate the worth of preventative healthcare measures to the public. Show more

Keywords: Alzheimer's disease, amyloid, health, hypoxia, metabolism, oxidative stress, public risk factors, therapeutics

DOI: 10.3233/JAD-2011-110089

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 571-581, 2011

Authors: Seppälä, Toni T. | Koivisto, Anne M. | Hartikainen, Päivi | Helisalmi, Seppo | Soininen, Hilkka | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Longitudinal changes of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) have been studied, but there are few consistent conclusions and even less is known about their variation during the different stages of the disease. We hypothesized that changes in CSF biomarker values would correlate with the progression of the cognitive decline in AD. One hundred and thirty-one memory clinic patients [56 AD, 57 mild cognitive impairment (MCI), 10 other neurological disorders, eight unimpaired subjects] underwent a clinical follow-up with repeated Mini-Mental Status Examination (MMSE) tests and two lumbar punctures with a median interval of 3 years. Levels of CSF …amyloid-β (Aβ)42 , tau, and p-tau-181 were measured using commercially available ELISA. Twenty-one of the MCI subjects progressed to AD, whereas 26 subjects remained stable and 56 subjects had AD already at the baseline. The subjects displaying the most rapid MMSE decline rate had the lowest baseline Aβ42 , highest tau, and highest p-tau-181 CSF concentrations. An annual decrease of 2.20 pg/ml/year in the CSF p-tau-181 concentration was seen in AD-AD patients (p = 0.001). The difference was significant compared to stable MCI-MCI (increase of 1.24 pg/ml/year, p = 0.001) and cognitively healthy (increase of 0.84 pg/ml/year, p = 0.013) subjects (p for group difference 0.004). The decrease rate of p-tau-181 correlated with the MMSE decrease rate in AD subjects (r = 0.579, p < 0.001). The CSF Aβ42 level decreased in the AD-AD group (decrease 11.9 pg/ml/year, p < 0.001). Concentrations of hyperphosphorylated tau decline in the late stages of the AD process. The decrease of p-tau-181 appears to correlate with cognitive functioning and probably reflects neuronal loss. More longitudinal studies of CSF biomarker dynamics are needed, especially in patients during the preclinical stage of the disease. Show more

Keywords: Alzheimer's disease, amyloid, biomarker, cerebrospinal fluid, CSF, longitudinal, mild cognitive impairment, tau

DOI: 10.3233/JAD-2011-101911

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 583-594, 2011

Authors: Wouters, Hans | van Campen, Jos | Appels, Bregje | Lindeboom, Robert | Buiter, Maarten | de Haan, Rob J. | Zwinderman, Aeilko H. | van Gool, Willem A. | Schmand, Ben

Article Type: Research Article

Abstract: Longer cognitive tests, such as the Alzheimer's disease assessment scale (ADAS-cog) or the Cambridge cognitive examination (CAMCOG), are more precise but less efficient than briefer tests, such as the Mini Mental State Examination (MMSE). We examined if computerized adaptive testing (CAT) of cognitive impairment can combine brevity with precision by tailoring a precise test to each individual patient. We conducted a prospective study of 84 participants [normal aging, n = 41; mild cognitive impairment (MCI), n = 21; dementia, n = 22]. CAT estimated a participant's ability during testing by selecting only items of appropriate difficulty from either the CAMCOG …or the CAMCOG supplemented with ADAS-cog items and neuropsychological tests (the CAMCOG-Plus). After tailored testing with CAT, the remaining CAMCOG and CAMCOG-Plus items not selected by CAT were administered. The time needed to complete the CAT was compared to that needed for the whole CAMCOG and CAMCOG-Plus. Results showed that testing time reductions achieved with CAT were 37% or more compared to the whole CAMCOG and 55% or more compared to the whole CAMCOG-Plus. Estimated ability levels with CAT were in excellent agreement with those based on the whole CAMCOG and CAMCOG-Plus (intraclass correlations 0.99 and 0.98, respectively). Diagnostic accuracy of detecting mild dementia and MCI seemed better for the CAT administered tests than for the MMSE, but the differences were not significant. We conclude that adaptive testing combines brevity with precision, especially in grading the severity of cognitive impairment. Show more

Keywords: Algorithms, Alzheimer's disease, amnesia, cognition disorders, dementia, logistic models, neuropsychology, vascular dementia

DOI: 10.3233/JAD-2011-101743

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 595-603, 2011

Authors: Nagele, Robert G. | Clifford, Peter M. | Siu, Gilbert | Levin, Eli C. | Acharya, Nimish K. | Han, Min | Kosciuk, Mary C. | Venkataraman, Venkat | Zavareh, Semah | Zarrabi, Shabnam | Kinsler, Kristin | Thaker, Nikhil G. | Nagele, Eric P. | Dash, Jacqueline | Wang, Hoau Y. | Levitas, Andrew

Article Type: Research Article

Abstract: Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β42 (Aβ42 ) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on …the intraneuronal deposition of soluble Aβ42 peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ42 accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ42 peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ42 accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ42 in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, amyloid, autoantibodies, autoimmunity, blood brain barrier, neurodegenerative disease

DOI: 10.3233/JAD-2011-110098

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 605-622, 2011

Authors: Barone, Eugenio | Di Domenico, Fabio | Cenini, Giovanna | Sultana, Rukhsana | Coccia, Raffaella | Preziosi, Paolo | Perluigi, Marzia | Mancuso, Cesare | Butterfield, D. Allan

Article Type: Research Article

Abstract: Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated …only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders. Show more

Keywords: Alzheimer's disease, biliverdin reductase, heme oxygenase, mild cognitive impairment, neurodegenerative disorders, oxidative stress

DOI: 10.3233/JAD-2011-110092

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 623-633, 2011

Authors: Turton, James C. | Bullock, James | Medway, Christopher | Shi, Hui | Brown, Kristelle | Belbin, Olivia | Kalsheker, Noor | Carrasquillo, Minerva M. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Younkin, Steven G. | Morgan, Kevin

Article Type: Research Article

Abstract: The missing heritability exhibited by late-onset Alzheimer's disease is unexplained and has been partly attributed to epistatic interaction. Methods available to explore this are often based on logistic regression and allow for determination of deviation from an expected outcome as a result of statistical epistasis. Three such methodologies including Synergy Factor and the PLINK modules, –epistasis and –fast-epistasis, were applied to study an epistatic interaction between interleukin-6 and interleukin-10. The models analyzed consisted of two synergistic interactions (SF ≈ 4.2 and 1.6) and two antagonistic interactions (SF ≈ 0.9 and 0.6). As with any statistical test, power to detect association …is paramount; and most studies will be underpowered for the task. However, the availability of large sample sizes through genome-wide association studies make it feasible to examine approaches for determining epistatic interactions. This study documents the sample sizes needed to achieve a statistically significant outcome from each of the methods examined and discusses the limitations/advantages of the chosen approaches. Show more

Keywords: Complex disorders, epistasis, LOAD, modeling, PLINK, synergy factor

DOI: 10.3233/JAD-2011-110197

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 635-644, 2011

Authors: Canepa, Elisa | Borghi, Roberta | Viña, Jose | Traverso, Nicola | Gambini, Juan | Domenicotti, Cinzia | Marinari, Umberto M. | Poli, Giuseppe | Pronzato, Maria A. | Ricciarelli, Roberta

Article Type: Research Article

Abstract: Accumulating data supports the concept that alterations of cholesterol metabolism might influence the development of Alzheimer's disease (AD), a neurodegenerative disorder characterized by progressive accumulation of amyloid-β (Aβ) peptides in the brain. Changes in the neuronal production of Aβ have been described as a function of cholesterol levels, thus suggesting a causal link between cholesterol homeostasis dysregulation and AD pathogenesis. Under physiological conditions, cholesterol uptake in the brain is efficiently prevented by the blood-brain barrier, and mature neurons are thought to rely on glial cells for their cholesterol supply. In the present study, we tested the hypothesis that Aβ may …serve as a signaling molecule capable of informing the astroglial network about the neuronal need for cholesterol. Collectively, our data bolster this hypothesis and demonstrate, for the first time, that Aβ42 exerts an inhibitory effect on the expression of the cholesterol transporter ABCA1 in cultured astrocytes. Accordingly, we also show that ABCA1 expression is reduced in the brain of AβPP/PS1 transgenic mice. These results provide a biological function for Aβ peptides and may help to define the pathogenic relationship between cholesterol metabolism in brain and AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, ATP-binding cassette transporter A1, sterols

DOI: 10.3233/JAD-2011-110053

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 645-653, 2011

Authors: Zhao, Wei-Qin | Toolan, Dawn | Hepler, Robert W. | Wolfe, Abigail L. | Yu, Yuanjiang | Price, Eric | Uebele, Victor N. | Schachter, Joel B. | Reynolds, Ian J. | Renger, John J. | McCampbell, Alexander | Ray, William J.

Article Type: Research Article

Abstract: Accumulation of small soluble assemblies of amyloid-β (Aβ)42 in the brain is thought to play a key role in the pathogenesis of Alzheimer's disease. As a result, there has been much interest in finding small molecules that inhibit the formation of synaptotoxic Aβ42 oligomers that necessitates sensitive methods for detecting the initial steps in the oligomerization of Aβ42 . Modeling suggests that oligomerized Aβ42 adopts a conformation in which the C-terminus is embedded in the center, whereas the N-terminus is exposed at the periphery of the oligomer. Here we report that an inverse change in Aβ42 …C-terminal and N-terminal epitope accessibility provides the basis of a sensitive method for assessing early steps in Aβ42 oligomerization. Using ELISA and AlphaLISA, we found that Aβ42 C-terminal immunoreactivity decreased in a time- and concentration-dependent manner under conditions favoring oligomerization. This reduction was accompanied by an increase in the N-terminal immunoreactivity, suggesting that assemblies with multiple exposed N-terminal epitopes were detected. Importantly the assay generates a robust window between monomers and oligomers at as low as 1 nM Aβ42 . Using this assay, known oligomerization inhibitors produced a dose-dependent unmasking of the Aβ42 C-terminal epitope. After automation, the assay proved to be highly reproducible and effective for high throughput screening of small molecules that inhibit Aβ42 oligomerization. Show more

Keywords: Alzheimer's disease, drug development, oligomer inhibitor

DOI: 10.3233/JAD-2011-102022

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 655-669, 2011

Authors: Schrijvers, Elisabeth M.C. | Direk, Nese | Koudstaal, Peter J. | Kirschbaum, Clemens | Hofman, Albert | Tiemeier, Henning | Breteler, Monique M.B.

Article Type: Research Article

Abstract: Higher levels of cortisol have been observed in persons with cognitive decline and dementia. It is unknown whether these higher levels are a cause or a consequence of disease. We investigated whether morning levels of serum cortisol were associated with cognitive function, cognitive decline, and the risk of dementia and Alzheimer's disease in the Rotterdam Study, a large prospective population based cohort study. Cortisol levels were assessed in fasting blood serum in 3341 participants, who were free of dementia at baseline (1997–1999). Cognitive function was assessed with a dedicated neuropsychological test battery at baseline and at follow-up examination (2002–2004). In …addition, the cohort was continuously monitored for incident dementia until January 1, 2007. After a mean follow-up of 7.1 years, 243 participants had developed dementia, of whom 210 were diagnosed with Alzheimer's disease. Morning serum levels of cortisol were neither related to cognitive function at baseline, nor to annual cognitive decline. There was no relation between serum levels of cortisol and the risk of developing dementia or Alzheimer's disease. These results suggest that that morning serum cortisol is not a causal factor in the development of dementia. Show more

Keywords: Alzheimer's disease, cognition, cortisol, dementia

DOI: 10.3233/JAD-2011-110224

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 671-677, 2011

Authors: Buschert, Verena C. | Friese, Uwe | Teipel, Stefan J. | Schneider, Philine | Merensky, Wibke | Rujescu, Dan | Möller, Hans-Jürgen | Hampel, Harald | Buerger, Katharina

Article Type: Research Article

Abstract: Recent studies have shown that patients with Alzheimer's disease (AD) and its possible prodromal stage mild cognitive impairment benefit from cognitive interventions. Few studies so far have used an active control condition and determined effects in different stages of disease. We evaluated a newly developed 6-month group-based multicomponent cognitive intervention in a randomized controlled pilot study on subjects with amnestic mild cognitive impairment (aMCI) and mild AD patients. Forty-three subjects with aMCI and mild AD were recruited. Primary outcome measures were change in global cognitive function as determined by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini Mental …Status Examination (MMSE). Secondary outcomes were specific cognitive and psychopathological ratings. Thirty-nine patients were randomized to intervention groups (IGs: 12 aMCI, 8 AD) and active control groups (CGs: 12 aMCI, 7 AD). At the end of the study, we found significant improvements in the IGMCI compared to the CGMCI in the ADAS-cog (p = 0.02) and for the secondary endpoint Montgomery Asberg Depression Rating Scale (MADRS) (p < 0.01) Effects on the MMSE score showed a non-significant trend (p = 0.07). In AD patients, we found no significant effect of intervention on the primary outcome measures. In conclusion, these results suggest that participation in a 6-month cognitive intervention can improve cognitive and non-cognitive functions in aMCI subjects. In contrast, AD patients showed no significant benefit from intervention. The findings in this small sample support the use of the intervention in larger scales studies with an extended follow-up period to determine long-term effects. Show more

Keywords: Alzheimer's disease, cognitive intervention, cognitive stimulation, cognitive training, mild cognitive impairment, stage-specific

DOI: 10.3233/JAD-2011-100999

Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 679-694, 2011