Volume 7, Number 3, June 2005

Pages 187-199
Hojjat Adeli, Samanwoy Ghosh-Dastidar, Nahid Dadmehr
Alzheimer’s Disease and Models of Computation: Imaging, Classification, and Neural Models
Abstract: Prediction or early-stage diagnosis of Alzheimer’s disease (AD) requires a comprehensive understanding of the underlying mechanisms of the disease and its progression. Researchers in this area have approached the problem from multiple directions by attempting to develop (a) neurological (neurobiological and neurochemical) models, (b) analytical models for anatomical and functional brain images, (c) analytical feature extraction models for electroencephalograms (EEGs), (d) classification models for positive identification of AD, and (e) neural models of memory and memory impairment in AD. This article presents a state-of-the-art review of research performed on computational modeling of AD and its markers. The review covers the following approaches: computer imaging, classification models, connectionist neural models, and biophysical neural models. It is concluded that a mixture of markers and a combination of novel computational techniques such as neural computing, chaos theory, and wavelets can increase the accuracy of algorithms for automated detection and diagnosis of AD.

Pages 201-212
Ana Gabriela Henriques, Sara C. T. S. Domingues, Margarida Fardilha, Edgar F. da Cruz e Silva, Odete A. B. da Cruz e Silva
Sodium azide and 2-deoxyglucose-induced cellular stress affects phosphorylation-dependent AßPP processing
Abstract: Production of the amyloid ß (Aß) peptide via altered metabolism of the amyloid ß-protein precursor (AßPP) appears to be a key event in the pathology of Alzheimer disease (AD). Accordingly, altered processing of AßPP was observed under conditions of abnormal cellular stress induced by sodium azide in the presence of 2-deoxy-D-glucose (2DG). As previously reported, the production of sAßPP (the secreted fragment of AßPP) was inhibited. However, our data further suggests that 2DG alone can account for most of the observed effects on AßPP processing in COS-1 cells and PC12 cells. It appears that 2DG interferes with the normal glycosylation of AßPP and its maturation process, having direct consequences on sAßPP production. Interestingly, PMA (phorbol 12-myristate 13-acetate)-induced sAßPP production was maintained under the stress conditions used, suggesting that potential non-amyloidogenic AßPP processing can still be favoured. This is of potential therapeutic interest, since it indicates that even under adverse stress conditions drugs such as PMA can affect AßPP processing, leading to increased sAßPP production and a concomitant reduction in Aß production. However, the induction of sAßPP production was not identical when the phosphatase inhibitor OA (okadaic acid) was used. In fact, the typical OA-induced increase in sAßPP production could be abolished under specific conditions. This constitutes an interesting precedent for the possible dissociation of the PMA and OA responses in terms of sAßPP production. The involvement of protein phosphatases, which are inhibited by OA, in AßPP processing, was reinforced by the increased co-localization of AßPP and PP1alpha (protein phosphatase 1alpha) at the cell surface upon exposure to OA and PMA. Overall, our results support the notion that signal transduction processes may be of particular relevance for our understanding of the molecular basis of AD, and for the design of rational signal transduction therapeutics.

Pages 213-220
B. Puig, I. Ferrer, R.F. Ludueña, J. Ávila
ßII-tubulin and phospho-tau aggregates in Alzheimer’s disease and Pick’s disease
Abstract: The expression of ßI-, ßII- and ßIII-tubulin isotypes was examined by immunohistochemistry in the entorhinal and transentorhinal cortices, hippocampus and dentate gyrus in normal human brains and in cases with Alzheimer’s disease (AD), Pick’s disease (PiD) and in argyrophilic grain disease (AGD). The results showed that ßII-tubulin predominated in the upper layers (mainly layer II) and ßIII-tubulin in the inner layers of the entorhinal and transentorhinal cortices in control brains. ßII-tubulin immunoreactivity was higher than ßIII-tubulin immunoreactivity in granular neurons of the dentate gyrus, whereas pyramidal neurons of the hippocampus proper were stained equally with anti-ßII-tubulin and ßIII-tubulin antibodies. No preferential layering distribution was observed for ßI-tubulin. Polymerization assays with tubulin peptides following the method of microtubule-associated protein displacement demonstrated that the ßI and ßIII isotypes have a higher binding capacity for tau than does the ßII isotype. Interestingly, about 60% of neurons with neurofibrillary tangles in layer II of the entorhinal and transentorhinal cortices in AD were selectively stained with anti-ßII-tubulin antibodies. Moderate ßII-tubulin immunoreactivity was also observed in Pick bodies in PiD. Taken together, these findings support the view that high ßII-tubulin content is a contributing factor in the formation of abnormal hyper-phosphorylated tau aggregates.

Pages 221-232
Milan Fiala, Justin Lin, John Ringman, Vali Kermani-Arab, George Tsao, Amish Patel, Albert S. Lossinsky, Michael C. Graves, Andrew Gustavson, James Sayre, Emanuela Sofroni, Tatiana Suarez, Francesco Chiappelli, George Bernard (Communicated by Craig Atwood)
Ineffective phagocytosis of amyloid-ß by macrophages of Alzheimer’s disease patients
Abstract: The defective clearance of amyloid-ß (Aß) in the brain of Alzheimer’s disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Aß but only inefficient clearance of Aß deposits. Neurons and neuronal nuclei, respectively, express interleukin-1ß and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology of Aß clearance, we examined Aß phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Aß followed by Aß degradation or export. AD monocytes show poor differentiation and only surface uptake of Aß and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Aß clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.

Page 233
Foreward: Challenging Views of Alzheimer’s Disease – 2004
J. Wesson Ashford, Keith A. Crutcher, Stephen R. Robinson, Mark A. Smith

Pages 235-239
Special Report from the Challenging Views of Alzheimer’s Disease
John C. Morris, Jeffrey Cummings
Mild Cognitive Impairment (MCI) Represents Early-Stage Alzheimer’s Disease
Introduction: Although the conclusive diagnosis of Alzheimer’s disease rests on clinicopathological correlation, much now is known about its clinical and behavioral symptoms. The current clinical diagnostic process can identify AD with high accuracy (90% or higher in autopsy-confirmed series from dementia research centers). Clinical diagnostic tools include a careful history of the presentation and course of dementia and potentially contributing conditions (e.g., stroke, depression, medications), objective tests of cognitive function, physical and neurological examinations, and a limited number of laboratory procedures (thyroid function tests, vitamin B12 levels, and neuroimaging). Standard diagnostic criteria and assessment procedures for AD have been published in a Practice Parameter by the American Academy of Neurology (AAN) and by the Clinical Practice Committee of the American Geriatrics Society. In spite of these published clinical diagnostic criteria, the expanding number of prevalent cases, and the availability of Food and Drug Administration (FDA) approved medications for the symptomatic treatment of AD, dementia remains notably under-recognized in the community. Forty-five percent of demented inpatients were not identified in one study, and memory loss was documented in only 23% of cognitively impaired patients in a primary care setting in another. There are continued efforts to develop brief diagnostic tools for dementia but as yet none have sufficient sensitivity, specificity, and “ease-of-use” to warrant widespread adoption by practitioners.

Pages 241-245
Special Report from the Challenging Views of Alzheimer’s Disease
Ronald C. Petersen, David Bennett
Mild Cognitive Impairment: Is it Alzheimer’s Disease or Not?
Abstract: In this discussion, the status of mild cognitive impairment (MCI) will be addressed from several perspectives. While some investigators maintain that MCI or its equivalent states actually represent fully developed Alzheimer’s disease (AD), others suggest that there must be an intermediate stage between the cognitive changes of aging and the very earliest manifestations of AD. Since AD is a degenerative disorder, by definition, it likely evolves over a period of months to years, or perhaps even longer. As such, there must be a prodromal state during which some of the clinical features of the disease are manifested but the fully developed syndrome is not present. Even if these mild features turn out to be related to neuritic plaques and neurofibrillary tangles, by current definitions, these persons do not yet meet accepted criteria for AD. We will address this topic from several different perspectives: clinical, neuroimaging, biomarkers, and neuropathology. We contend that this transitional state exists and the several lines of evidence demonstrated in the literature are consistent with this position. Ultimately, the discussion will revolve around the definition of AD.

Pages 247-253
Special Report from the Challenging Views of Alzheimer’s Disease
J. Wesson Ashford, Craig S. Atwood, John P. Blass, Richard L. Bowen, Caleb E. Finch, Khalid Iqbal, James A. Joseph, George Perry
What is Aging? What Is its Role in Alzheimer's Disease? What Can We Do About It?
Summary: Here we present a summary of the round-table discussion entitled “What is Aging, What Is its Role in Alzheimer's Disease and What Can We Do About It?” from the recent conference, Challenging Views of Alzheimer’s Disease – 2004, held in Philadelphia, July 2004. Eight scientists specializing in aging, Alzheimer’s disease, and neurobiology discussed the definition of aging, how aging theory relates to understanding Alzheimer’s disease, and what insights from understanding this relationship could be applied to developing means to treat or prevent this disease.

Pages 255-262
Transcript: Alzheimer Research Forum Live Discussion
Memantine: Implications for Treating Alzheimer's

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