Journal of Alzheimer's Disease - Volume 21, issue 4

Article Type: Obituary

DOI: 10.3233/JAD-2010-101547

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1037-1037, 2010

Authors: Daulatzai, Mak Adam

Article Type: Review Article

Abstract: Aging is a consequence of progressive decline in special and somatosensory functions and specific brain stem nuclei. Many senescent stigmata, including hypoxia, hypoxemia, depressed cerebral blood flow and glucose metabolism, diseases of senescence, and their medications all enhance hypothermia as do alcohol, cold environment, and malnutrition. Hypothermia is a critical factor having deleterious impact on brain stem and neocortical functions. Additionally, anesthesia in elderly also promotes hypothermia; anesthetics not only cause consciousness (sensory and motor) changes, but memory impairment as well. Anesthesia inhibits cholinergic pathways, reticular and thalamocortical systems, cortico-cortical connectivity, and causes post-operative delirium and cognitive dysfunction. Increasing evidence …indicates that anesthetic exposures may contribute to dementia onset and Alzheimer's disease (AD) in hypothermic elderly. Inhaled anesthetics potentiate caspases, BACE, tau hyperphosphorylation, and apoptosis. This paper addresses the important question: “Why do only some elderly fall victim to AD”? Based on information on the pathogenesis of early stages of cognitive dysfunction in elderly (i.e., due to senescent stigmata), and the effects of anesthesia superimposed, a detailed plausible neuropathological substrate (mechanism/pathway) is delineated here that reveals the possible cause(s) of AD. Basically, it encompasses several risk factors for cognitive dysfunction during senescence plus several hypothermia-enhancing routes; they all converge and tip the balance towards dementia onset. This knowledge of the confluence of heterogeneous risk factors in perpetuating dementia relentlessly is of importance in order to: (a) avoid their convergence; (b) take measures to stop/reverse cognitive dysfunction; and (c) to develop therapeutic strategies to enhance cognitive function and attenuate AD. Show more

Keywords: Aging, amyloid-β, anesthesia, dementia, hypothermia, neurofibrillary tangles

DOI: 10.3233/JAD-2010-100267

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1039-1063, 2010

Authors: Wang, Yan-Jiang | Zhou, Hua-Dong | Zhou, Xin-Fu

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is characterized by the deposition of amyloid plaques, loss of neurons, neuritic degeneration, accumulation of fibrillary tangles in neurons, and a progressive loss of cognitive function. Amyloid-β peptide (Aβ) appears to play a pivotal role in the development of AD. Clearance of Aβ from the brain represents an important therapeutic strategy for prevention and treatment of AD. Immunotherapy targeting Aβ is effective to remove the peptide from the brain. However, it is associated with detrimental adverse effects, such as autoimmune meningoencephalitis and microhemorrhage. These are presumably the results of brain infiltration of provoked autoimmune T lymphocytes in …response to Aβ vaccination and release of proinflammatory cytokines from microglia activated by the immune complex of Aβ and antibodies. An improvement of the safety of the immunotherapy is a major goal of the immunotherapy study. Here, we review the mechanisms involved in modified immunological strategies, as well as their adverse effects. We discuss the following: the development of B epitope vaccines to avoid activation of autoimmune T lymphocytes; DNA vaccines containing appropriate immunostimulatory and immunomodulatory sequences to induce the desired humoral immune responses; antibody modifications to avoid activation of microglia and subsequent release of proinflammatory cytokines; single chain antibody-based gene therapy; immunotherapy targeting Aβ oligomers; modulation of antibody delivery approach and dose; and application of autoantibodies against Aβ. These ultimately represent future directions of therapeutic approaches toward safer and effective Aβ clearance. Show more

Keywords: Alzheimer's disease, amyloid-β, autoantibody, immunotherapy, oligomer, vaccine, single chain antibody

DOI: 10.3233/JAD-2010-100195

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1065-1075, 2010

Authors: Modrego, Pedro J.

Article Type: Review Article

Abstract: Depression is a comorbid condition in Alzheimer's disease (AD) with negative consequences in patients and caregivers. Pathophysiology and optimal treatment are matters to be elucidated. A search of articles dealing with depression in AD was conducted in MEDLINE with special attention to epidemiology, pathophysiology, and treatment. Depression may predate dementia and tends to occur in up to 50% of AD patients with a decrease of noradrenalin and serotonin in the brain being the most plausible cause. Only 7 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression were found: 4 with sertraline, 1 with fluoxetine, 1 …with imipramine, and another one with clomipramine. The total number of treated patients was 318. The weighted odds ratio (OR) was calculated with the method of Mantel-Haenszel. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are better than placebo in treating depression in AD (weighted OR: 1.82, 95% CI: 1.13–2.96), with sertraline being one of the most used drugs. The differences were significant in 2 trials and not significant in four. The magnitude of effect is globally modest. Moreover, it is noteworthy mentioning the high rates of response to placebo in most studies. Depression is one of the most frequent behavioral symptoms in AD. Although antidepressants may work in AD, given the small number of patients treated, the effect is unclear. Further large randomized controlled clinical trials are warranted in order to know the best drug to begin with and the actual degree of efficacy. Show more

Keywords: Alzheimer's disease, depression, randomized trials

DOI: 10.3233/JAD-2010-100153

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1077-1087, 2010

Authors: Trepanier, Catherine H. | Milgram, Norton W.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is currently treated with cholinergic and glutamatergic therapies, which provide symptomatic benefit but do not reverse the underlying pathology or cognitive deficits. The prevalence of AD is expected to triple over the next 50 years, creating an urgency to develop effective "disease-modifying" therapies to reduce the economic burden of this devastating disorder. One of the main areas of therapeutic focus has been an anti-inflammatory strategy based on an inflammatory hypothesis of AD. This hypothesis originated from epidemiological evidence that long-term exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) protected against the development of AD. However, large-scale double-blind placebo-controlled clinical …trials have not supported the use of NSAIDS in treating AD. The following review outlines epidemiological, preclinical, and clinical evidence evaluating the efficacy of various NSAIDs and selective COX-2 inhibitors in AD. We also review recent anecdotal data with the TNF-α inhibitor, etanercept, and discuss possible explanations for the failure of preclinical data to translate into successful clinical trials. Show more

Keywords: Alzheimer's disease, anti-inflammatories, COX-2 inhibitors, neuroinflammation, NSAIDs, TNF-α

DOI: 10.3233/JAD-2010-090667

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1089-1099, 2010

Authors: Gray, Emma H. | De Vos, Kurt J. | Dingwall, Colin | Perkinton, Michael S. | Miller, Christopher C.J.

Article Type: Short Communication

Abstract: The copper chaperone for superoxide dismutase (CCS) binds to both the β-site AβPP cleaving enzyme (BACE1) and to the neuronal adaptor protein X11α. BACE1 initiates AβPP processing to produce the amyloid-β (Aβ) peptide deposited in the brains of Alzheimer's disease patients. X11α also interacts directly with AβPP to inhibit Aβ production. However, whether CCS affects AβPP processing and Aβ production is not known. Here we show that loss of CCS increases Aβ production in both CCS knockout neurons and CCS siRNA-treated SHSY5Y cells and that this involves increased AβPP processing at the BACE1 site.

Keywords: BACE1, copper, copper chaperone for superoxide dismutase, Cu/Zn superoxide dismutase, munc18 interacting protein-1, X11α

DOI: 10.3233/JAD-2010-100717

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1101-1105, 2010

Authors: Fu, Zheng-Qi | Yang, Ying | Song, Jie | Jiang, Qian | Liu, Zan-Chao | Wang, Qun | Zhu, Ling-Qiang | Wang, Jian-Zhi | Tian, Qing

Article Type: Research Article

Abstract: Abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is indicated to play an important role in neurodegeneration and activation of glycogen synthase kinase-3β (GSK-3β), an integral kinase in tau phosphorylation. To explore the effect of ER stress on tau phosphorylation, we treated cultured cells (HEK293 and SH-SY5Y cells) and rat brain with thapsigargin, an ER stress inducer. We found that the phosphorylation level of tau was significantly increased after thapsigargin treatment. By using a cell-free reconstitution system, we also observed that co-culture of the thapsigargin-treated …ER fraction from HEK293/wt (without tau) with cytoplasm prepared from HEK293/tau induced an increased tau phosphorylation. Concurrently, activation of GSK-3β as evidenced by an increased phospho-GSK-3β at Tyr-216 and decreased phospho-GSK-3β at Ser-9 both in vitro and in vivo was detected. Application of lithium chloride, a GSK-3 inhibitor, could efficiently attenuate the thapsigargin-induced tau hyperphosphorylation with suppressed activation of GSK-3β in cell cultures and rat brains. Our data provide further evidence supporting the role of ER stress in tau hyperphosphorylation and the protective role of lithium. Show more

Keywords: ndoplasmic reticulum, glycogen synthase kinase-3β, phosphorylation, tau, thapsigargin

DOI: 10.3233/JAD-2010-100687

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1107-1117, 2010

Authors: Hertze, Joakim | Minthon, Lennart | Zetterberg, Henrik | Vanmechelen, Eugeen | Blennow, Kaj | Hansson, Oskar

Article Type: Research Article

Abstract: In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42 , Aβ40 , Aβ38 , sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n= 94), MCI (n= 166), depressive disorder (n= 29), and cognitively healthy controls (n= 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable …after a follow-up of 4.7 years (range 3.0–7.2). Optimal cut-offs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cut-offs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6–58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, cerebrospinal fluid, early diagnosis, mild cognitive impairment

DOI: 10.3233/JAD-2010-100207

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1119-1128, 2010

Authors: Firbank, Michael J. | Blamire, Andrew M. | Teodorczuk, Andrew | Teper, Emma | Burton, Emma J. | Mitra, Dipayan | O'Brien, John T.

Article Type: Research Article

Abstract: We used high resolution (0.3 mm in-plane) coronal 3T magnetic resonance (MR) imaging of the medial temporal lobe in 16 subjects with Alzheimer's disease (AD), 16 with dementia with Lewy bodies (DLB), and 16 similarly aged healthy subjects. On the anterior section of the hippocampus body, regions of interest were manually drawn blind to diagnosis on the CA1, CA2, and CA3/4 subregions, and the width of the subiculum and entorhinal cortex was measured. Controlling for intracranial volume, age, and years of education, we found the subiculum thickness was significantly reduced in AD (2.03 ± 0.29 mm) compared to both control …(2.37 ± 0.28 mm, p = 0.008) and DLB (2.35 ± 0.24 mm, p = 0.001) subjects. The area of CA1 was likewise reduced in AD compared to controls and DLB. In the hippocampus images, a hypointense line is visible between CA1 and CA3/4. This line was significantly less distinct in AD, suggesting disease related changes to this region. Future studies should investigate whether subiculum thickness or the hypointense line could be a diagnostic feature to help discriminate AD from DLB. Show more

Keywords: Alzheimer's disease, dementia with Lewy bodies, hippocampus, MRI, subiculum

DOI: 10.3233/JAD-2010-100138

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1129-1140, 2010

Authors: Julkunen, Valtteri | Niskanen, Eini | Koikkalainen, Juha | Herukka, Sanna-Kaisa | Pihlajamäki, Maija | Hallikainen, Merja | Kivipelto, Miia | Muehlboeck, Sebastian | Evans, Alan C. | Vanninen, Ritva | Soininen, Hilkka

Article Type: Research Article

Abstract: In this study, we analyzed differences in cortical thickness (CTH) between healthy controls (HC), subjects with stable mild cognitive impairment (S-MCI), progressive MCI (P-MCI), and Alzheimer's disease (AD), and assessed correlations between CHT and clinical disease severity, education, and apolipoprotein E4 (APOE) genotype. Automated CTH analysis was applied to baseline high-resolution structural MR images of 145 subjects with a maximum follow-up time of 7.4 years pooled from population-based study databases held in the University of Kuopio. Statistical differences in CTH between study groups and significant correlations between CTH and clinical and demographic factors were assessed and displayed on a cortical …surface model. Compared to HC group (n =26), the AD (n = 21) group displayed significantly reduced CTH in several areas of frontal and temporal cortices of the right hemisphere. Higher education and lower MMSE scores were correlated with reduced CTH in the AD group, whereas no significant correlation was found between CDR-SB scores or APOE genotype and CTH. The P-MCI group demonstrated significantly reduced CTH compared to S-MCI in frontal, temporal and parietal cortices even after statistically adjusting for all confounding variables. Ultimately, analysis of CTH can be used to detect cortical thinning in subjects with progressive MCI several years before conversion and clinical diagnosis of AD dementia, irrespective of their cognitive performance, education level, or APOE genotype. Show more

Keywords: Alzheimer's disease, apolipoprotein E, cortical thickness, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2010-100114

Citation: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1141-1151, 2010