Journal of Alzheimer's Disease - Volume 17, issue 4

Authors: Takashima, Akihiko

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is clinically characterized as a progressive dementia starting with memory dysfunction and characterized pathologically as neurodegeneration accompanied by deposition of amyloid-β, neurofibrillary tangles, and neuronal loss. AD research has endeavored to explain the clinical symptoms of AD through pathological changes and to develop various therapies for AD. Fulfillment of these goals, however, remains on the horizon. In this article, I review the relationship between neuropathological changes that occur in the brain and clinical progression of AD, and propose a hypothesis that brain aging, characterized by neurofibrillary tangles in entorhinal cortex, is pre-requisite for development of AD.

Keywords: Amyloid-β, dementia, tau

DOI: 10.3233/JAD-2009-1090

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 729-736, 2009

Authors: Swerdlow, Russell H.

Article Type: Review Article

Abstract: Mitochondria are physically or functionally altered in many neurodegenerative diseases. This is the case for very rare neurodegenerative disorders as well as extremely common age-related ones such as Alzheimer's disease and Parkinson's disease. In some disorders very specific patterns of altered mitochondrial function or systemic mitochondrial dysfunction are demonstrable. Some disorders arise from mitochondrial DNA mutation, some from nuclear gene mutation, and for some the etiology is not definitively known. This review classifies neurodegenerative diseases using mitochondrial dysfunction as a unifying feature, and in doing so defines a group of disorders called the neurodegenerative mitochondriopathies. It discusses what mitochondrial abnormalities …have been identified in various neurodegenerative diseases, what is currently known about the mitochondria-neurodegeneration nexus, and speculates on the significance of mitochondrial function in some disorders not classically thought of as mitochondriopathies. Show more

Keywords: Alzheimer's disease, cybrid, mitochondria, mitochondriopathy, neurodegeneration, neurodegenerative, Parkinson's disease

DOI: 10.3233/JAD-2009-1095

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 737-751, 2009

Authors: Pandey, Janardan P.

Article Type: Research Article

Abstract: There is growing body of evidence for the involvement of herpes simplex virus type 1 (HSV1) in the etiology of Alzheimer's disease (AD). HSV1 has evolved strategies for decreasing the efficacy of the host immune response and interfering with viral clearance. Based on their putative role as the modulators of these immune avoidance strategies, I hypothesize that immunoglobulin (Ig) GM genes – genetic markers of IgG heavy chains located on chromosome 14 – are functional risk and protective factors for AD. Results from genome-wide association and linkage studies in support of this hypothesis, testable predictions, and possible therapeutic implications are …discussed. Show more

Keywords: Antibody dependent cellular cytotoxicity, Fcγ receptor, GM allotypes, herpes simplex virus type 1, immune evasion

DOI: 10.3233/JAD-2009-1094

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 753-756, 2009

Authors: Imbimbo, Bruno P.

Article Type: Article Commentary

Abstract: There has been a lot of disappointment surrounding the recent failure of the largest ever study in patients with Alzheimer's disease (AD) with tarenflurbil, a compound believed to modulate the activity of γ-secretase, the pivotal enzyme that generates the amyloid-β (Aβ) peptide from the amyloid-β protein precursor. What are the reasons for this setback after the previous apparently encouraging results in a Phase II study? A straightforward explanation of this failure is that the γ-secretase is not the right target for therapy or that, in general, blocking Aβ does not produce clinical benefits in AD. If one still accepts a …physiopathological role of Aβ in AD, tarenflurbil could not be the right compound because of its weak pharmacological activity as an Aβ1-42 lowering agent and its poor brain penetration. In addition, based on previous negative results with several anti-inflammatory drugs in AD, it is hypothesized that the residual anti-inflammatory activity of tarenflurbil may have a detrimental effect on disease progression. Show more

Keywords: Alzheimer's disease, amyloid-β, anti-inflammatory agent, clinical trial, γ-secretase, tarenflurbil

DOI: 10.3233/JAD-2009-1092

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 757-760, 2009

Authors: Nobili, Flavio | De Carli, Fabrizio | Frisoni, Giovanni B. | Portet, Florence | Verhey, Frans | Rodriguez, Guido | Caroli, Anna | Touchon, Jacques | Morbelli, Silvia | Guerra, Ugo P. | Dessi, Barbara | Brugnolo, Andrea | Visser, Pieter Jelle

Article Type: Research Article

Abstract: Baseline brain single photon emission computed tomography (SPECT) was evaluated in eighty subjects with mild cognitive impairment (MCI) who were followed for a mean of about two years, when twelve patients developed Alzheimer's disease (AD), nineteen showed memory decline (D), and forty-three had normal cognition assessment (stable: S) (six drop-out). Volumetric Regions of Interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures showed significant effects for both the group (S, D, and AD; p < 0.004) and VROI (p < 0.0001) factors, with significant group*region interaction (p < 0.01). At post-hoc comparison, …hippocampal VROIs values were lower in AD than in D and S, while parietal VROIs values were lower in D and AD than in S. These four VROI significantly correlated with verbal delayed recall score at follow-up visit. Receiver operating characteristic (ROC) curves for the mean hippocampal VROI value showed 0.81 sensitivity with 0.86 specificity in separation of S+D from AD (p < 0.0001), and 0.69 sensitivity with 0.75 specificity in separation of S from D+AD (p < 0.0002). ROC curves for the mean parietal VROI value showed 0.62 sensitivity with 0.70 specificity in separation of S from D+AD (p < 0.0002). Baseline SPECT can support outcome prediction in subjects with MCI. Show more

Keywords: Alzheimer's disease, amnestic MCI, brain SPECT, cognitive decline, non-amnestic MCI, subjective cognitive impairment

DOI: 10.3233/JAD-2009-1091

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 761-772, 2009

Authors: Simón, Ana María | de Maturana, Rakel López | Ricobaraza, Ana | Escribano, Luis | Schiapparelli, Lucio | Cuadrado-Tejedor, Mar | Pérez-Mediavilla, Alberto | Avila, Jesús | Del Río, Joaquín | Frechilla, Diana

Article Type: Research Article

Abstract: Synapse loss occurs early in Alzheimer's disease (AD) and is considered thebest pathological correlate of cognitive decline. Ephrins and Eph receptorsare involved in regulation of excitatory neurotransmission and play a rolein cytoskeleton remodeling. We asked whether alterations in Eph receptorscould underlie cognitive impairment in an AD mouse model overexpressinghuman amyloid-β protein precursor (hAβPP) with familialmutations (hAβPPswe-ind mice). We found that EphA4 and EphB2receptors were reduced in the hippocampus before the development of impairedobject recognition and spatial memory. Similar results were obtained inanother line of transgenic AβPP mice, Tg2576. A reduction in Ephreceptor levels was also found in postmortem hippocampal …tissue frompatients with incipient AD. At the time of onset of memory decline inhAβPPswe-ind mice, no change in surface expression of AMPA orNMDA receptor subunits was apparent, but we found changes in Eph-receptordownstream signaling, in particular a decrease in membrane-associatedphosho-cofilin levels that may cause cytoskeletal changes and disruptedsynaptic activity. Consistent with this finding, Eph receptor activation incell culture increased phosho-cofilin levels. The results suggest thatalterations in Eph receptors may play a role in synaptic dysfunction in thehippocampus leading to cognitive impairment in a model of AD. Show more

Keywords: Alzheimer's disease, cofilin, ephrin, Eph receptor, glutamate receptor, LIM-kinase, memory, p21-activated kinase

DOI: 10.3233/JAD-2009-1096

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 773-786, 2009

Authors: Ampuero, Israel | Alegre-Abarrategui, Javier | Rodal, Izaskun | España, Antonio | Ros, Raquel | Sendón, José Luis Lopez | Galloway, Eva García | Cervelló, Ángeles | Belén Caminero, Ana | Zabala, Antxon | Erro, Elena | Jarauta, Fernando | Morlán, Lorenzo | López-Valdés, Eva | Aladro, Yolanda | Seijo, Manuel | Rivas, Guillermo García | Muñoz, David G. | de Yébenes, Justo García

Article Type: Research Article

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic arteriopathy related to Notch3 mutations, is difficult to diagnosis. The goal of this study was to determine the value of clinical, immunohistochemical, and molecular techniques for the diagnosis of CADASIL. Clinical features and the immunohistochemical and molecular findings in 200 subjects with suspected CADASIL in whom 93 biopsies and 190 molecular studies are reported. Eighteen pathogenic mutations of the Notch3 gene, six of them previously unreported, were detected in 67 patients. The clinical features did not permit differentiation between CADASIL and CADASIL-like syndromes. The sensitivity and specificity of …the skin biopsies was 97.7% and 56.5%, respectively, but increased to 100% and 81.5%, respectively, in cases with proven family history. In conclusion, a clinical diagnosis of CADASIL is difficult to determine and confirmatory techniques should be used judiciously. Show more

Keywords: CADASIL, familial stroke with dementia, Notch3, NOTCH3 immunostaining

DOI: 10.3233/JAD-2009-1112

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 787-794, 2009

Authors: Vega, Lourdes | Arroyo, Ángel A. | Tabernero, Arantxa | Medina, José M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is the main component of senile plaques, one of the hallmarks of Alzheimer's disease. Our results showed that Aβ25-35 decreased neuronal viability while it increased generation of reactive oxygen species (ROS). Under these circumstances, albumin (BSA) prevented ROS production and neuronal death in a dose- and time-dependent manner. In addition, BSA partially prevented the decrease in the expression of GAP-43, MAP-2, and tubulin, and the phosphorylation of tau protein caused by Aβ, suggesting that BSA protects against the loss of plasticity caused by the peptide. Our findings suggest that BSA exerts its protective effect by binding to …Aβ in an equimolecular way, which prevents heterodimer (Aβ-BSA) entry into neurons. In fact, BSA prevented Aβ internalization, as shown by confocal immunocytochemistry, suggesting that BSA causes its protective effect by sequestrating Aβ, which cannot reach its intracellular targets. This is consistent with the idea that Aβ must enter neurons to exert its deleterious effects. Show more

Keywords: Albumin, Alzheimer's disease, amyloid-β, antioxidant, neuroprotector

DOI: 10.3233/JAD-2009-1093

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 795-805, 2009

Authors: Taylor, Jr., Donald H. | Østbye, Truls | Langa, Kenneth M. | Weir, David | Plassman, Brenda L.

Article Type: Research Article

Abstract: Our study estimates the sensitivity and specificity of Medicare claims to identify clinically-diagnosed dementia, and documents how errors in dementia assessment affect dementia cost estimates. We compared Medicare claims from 1993–2005 to clinical dementia assessments carried out in 2001–2003 for the Aging Demographics and Memory Study (ADAMS) cohort (n = 758) of the Health and Retirement Study. The sensitivity and specificity of Medicare claims was 0.85 and 0.89 for dementia (0.64 and 0.95 for AD). Persons with dementia cost the Medicare program (in 2003) $7,135 more than controls (P < 0.001) when using claims to identify dementia, compared to $5,684 …more when using ADAMS (P < 0.001). Using Medicare claims to identify dementia results in a 110% increase in costs for those with dementia as compared to a 68% increase when using ADAMS to identify disease, net of other variables. Persons with false positive Medicare claims notations of dementia were the most expensive group of subjects ($11,294 versus $4,065, for true negatives P < 0.001). Medicare claims overcount the true prevalence of dementia, but there are both false positive and negative assessments of disease. The use of Medicare claims to identify dementia results in an overstatement of the increase in Medicare costs that are due to dementia. Show more

Keywords: Dementia costs, medicare, sensitivity, specificity

DOI: 10.3233/JAD-2009-1099

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 807-815, 2009

Authors: de la Monte, Suzanne M. | Tong, Ming

Article Type: Research Article

Abstract: Streptozotocin (STZ) is a nitrosamine-related compound that causes Alzheimer's disease (AD)-type neurodegeneration with cognitive impairment, brain insulin resistance, and brain insulin deficiency. Nitrosamines and STZ mediate their adverse effects by causing DNA damage, oxidative stress, lipid peroxidation, pro-inflammatory cytokine activation, and cell death, all of which occur in AD. We tested the hypothesis that exposure to N-nitrosodiethylamine (NDEA), which is widely present in processed/preserved foods, causes AD-type molecular and biochemical abnormalities in central nervous system (CNS) neurons. NDEA treatment of cultured post-mitotic rat CNS neurons (48 h) produced dose-dependent impairments in ATP production and mitochondrial function, and increased levels of …8-hydroxy-2'-deoxyguanosine, 4-hydroxy-2-nonenal, phospho-tau, amyloid-β protein precursor-amyloid-β (AβPP-Aβ), and ubiquitin immunoreactivity. These effects were associated with decreased expression of insulin, insulin-like growth factor (IGF)-I, and IGF-II receptors, and choline acetyltransferase. Nitrosamine exposure causes neurodegeneration with a number of molecular and biochemical features of AD including impairments in energy metabolism, insulin/IGF signaling mechanisms, and acetylcholine homeostasis, together with increased levels of oxidative stress, DNA damage, and AβPP-Aβ immunoreactivity. These results suggest that environmental exposures and food contaminants may play critical roles in the pathogenesis of sporadic AD. Show more

Keywords: Alzheimer's disease, diabetes mellitus, environmental toxin, neurodegeneration, nitrosamine

DOI: 10.3233/JAD-2009-1098

Citation: Journal of Alzheimer's Disease, vol. 17, no. 4, pp. 817-825, 2009