Journal of Alzheimer's Disease - Volume 21, issue 3

Authors: Huang, Tina L.

Article Type: Review Article

Abstract: The precipitous decline of memory and independence associated with cognitive decline, dementia, and Alzheimer's disease is emotionally and financially devastating to patients, their families, and caretakers. Studies from animal models and cell cultures have shown that omega-3 fatty acids (n-3 FAs) are neuroprotective during development and aging. Numerous epidemiologic, postmortem, and clinical trials have been published on fish or n-3 FAs and Alzheimer's disease, dementia, or cognitive decline. Yet results across the literature in humans are inconsistent and thus difficult to interpret. This review provides background and context needed for interpretation of the findings, summaries of the literature grouped by …longitudinal studies of fish, dietary n-3 FAs, blood levels of fatty acids, postmortem studies, and clinical trials, and subsequent interpretation of findings. Possible reasons for discrepancies in the literature are presented throughout, and conclusions suggest directions for future research. Show more

Keywords: Alzheimer's disease, cognitive decline, dementia, fish, omega-3 fatty acids

DOI: 10.3233/JAD-2010-090934

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 673-690, 2010

Authors: Panza, Francesco | Frisardi, Vincenza | Capurso, Cristiano | Imbimbo, Bruno P. | Vendemiale, Gianluigi | Santamato, Andrea | D'Onofrio, Grazia | Seripa, Davide | Sancarlo, Daniele | Pilotto, Alberto | Solfrizzi, Vincenzo

Article Type: Review Article

Abstract: A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer's disease, AD) or vascular origin (vascular dementia, VaD). At present, cumulative evidence suggests that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome (MetS) has been associated with the risk of cognitive decline, overall dementia, and VaD, but contrasting findings also existed on the possible role of MetS in AD. If MetS is associated with increased risk of developing cognitive impairment, regardless …of mechanism, then early identification and treatment of these individuals at risk might offer new avenues for disease-course modification. Strategies towards early and effective risk factor management could be of value in reducing risk of metabolic and cognitive decline. Future research is needed to confirm the association between MetS and cognitive impairment and to determine the exact mechanism linking them. Such would provide important insights into the causes and interdependencies of predementia and dementia syndromes, and inspire novel strategies for treating and preventing these disorders. At present, vascular risk factor and MetS management could be employed to delay the onset of dementia syndromes or to prevent the progression of predementia syndromes. In the future, trials could be undertaken to determine whether modifications of these risk factors, including inflammation, could lower risk of developing cognitive decline. Show more

Keywords: Alzheimer's disease, dementia, diabetes mellitus, HDL cholesterol, hypertension, hypertriglyceridemia, metabolic syndrome, mild cognitive impairment, obesity, predementia syndromes, vascular dementia, vascular risk factors

DOI: 10.3233/JAD-2010-091669

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 691-724, 2010

Authors: Brown, William R.

Article Type: Review Article

Abstract: String vessels are thin connective tissue strands, remnants of capillaries, with no endothelial cells; they do not carry blood flow. They occur in numerous species, particularly in the central nervous system, but can occur in any tissue where capillaries have died. String vessels are often associated with pathologies such as Alzheimer's disease, ischemia, and irradiation, but are also found in normal human brains from preterm babies to the aged. They provide a record of the original blood vessel location, but gradually disappear after months or years. There have been numerous studies of string vessels (acellular capillaries) in the retina, because …retinal vessels can be seen in great detail in whole mounts after trypsin digestion. Capillary regression occurs by apoptosis, synchronously along capillary segments, with macrophages engulfing apoptotic endothelial cells. Macrophages may cause the apoptosis, or the regression may be triggered by loss of the endothelial cell survival factor VEGF. VEGF expression is induced by hypoxia and promotes capillary growth. Cessation of blood flow eliminates the shear stress that helps maintain endothelial cell survival. Capillaries can re-grow by proliferation and migration of endothelial cells into empty basement membrane tubes, which provide a structural scaffold, replete with signaling molecules. This is a problem in tumor control, but useful for recovery from capillary loss. There is an age-related waning of VEGF expression in response to hypoxia. This causes an age-related decline in cerebral angiogenesis and results in neuronal loss. It may also contribute to the proposed age-related loss of brain reserve. Show more

Keywords: Alzheimer's disease, angiogenesis, basement membranes, capillary loss, intervascular strand, leukoaraiosis, retinal blood vessels, string vessels, vascular dementia

DOI: 10.3233/JAD-2010-100219

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 725-739, 2010

Authors: Singh, Manjeet | Nam, Dang Thanh | Arseneault, Madeleine | Ramassamy, Charles

Article Type: Review Article

Abstract: Abundant data consistently support the idea that oxidative stress occurs and is a constant feature of Alzheimer's disease (AD). Some recent evidence indicated that phenomenon is an early event and might be implicated in the pathogenesis of this disease. Lipid peroxidation leads to the formation of a number of aldehydes by-products, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), and acrolein. The most abundant aldehydes are HNE and MDA while acrolein is the most reactive. Increased levels of specific HNE-histidine and glutathione-HNE Michael adducts in AD brain has been reported. Proteomic analysis demonstrated a large number of protein-bound HNE in AD brain. F2-isoprostanes …(F2-IsoPs) levels and neuroprostanes were also significantly increased in mild cognitive impairment (MCI) patients and in late-stage AD. In brain from patients with AD, acrolein has been found to be elevated in hippocampus and temporal cortex where oxidative stress is high. Due to its high reactivity, acrolein is not only a marker of lipid peroxidation but also an initiator of oxidative stress by adducting cellular nucleophilic groups found on proteins, lipids, and nucleic acids. Interestingly, data indicates that lipid peroxidation occurs in the brain of MCI and also in preclinical AD patients suggesting that oxidative damage may play an early role in the pathogenesis of AD. In this review, we will summarize some mechanisms implicated in the toxicity of by-products of lipid peroxidation such as IsoPs, HNE, and acrolein and their implication in AD. Show more

Keywords: Arachidonic acid, docosahexaenoic acid, 4-hydroxy-nonenal, isoprostanes, neuroprostanes, oxidative stress, polyamines

DOI: 10.3233/JAD-2010-100405

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 741-756, 2010

Authors: Sinning, Mariana | van Rooyen, Jan Piere | Venegas-Francke, Pablo | Vásquez, Carolina | Behrens, María Isabel | Ramírez, Alfredo

Article Type: Short Communication

Abstract: Autosomal dominant early-onset Alzheimer's disease (ADEOAD) is associated predominantly with mutations in the genes that codify for presenilin 1 (PSEN1). Only a few ADEOAD families have been reported from Latin America. This is an extended Chilean pedigree affected by ADEOAD along 4 generations. The age of onset of dementia was between 38 and 42 years. Early manifestations were anxiety and depression. Mutation analysis revealed a heterozygous G to C transversion at position 438 of the mRNA in PSEN1 in all affected members. This is the first report of a Chilean family with ADEOAD to include mutation analysis.

Keywords: Alzheimer's disease, early-onset Alzheimer's disease (ADEOAD), presenilin 1, PSEN 1 protein

DOI: 10.3233/JAD-2010-100135

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 757-761, 2010

Authors: Sarajärvi, Timo | Helisalmi, Seppo | Antikainen, Leila | Mäkinen, Petra | Koivisto, Anne Maria | Herukka, Sanna-Kaisa | Haapasalo, Annakaisa | Soininen, Hilkka | Hiltunen, Mikko

Article Type: Short Communication

Abstract: Alzheimer's disease (AD) is a genetically complex disorder encompassing several individual susceptibility genes with low risk effects. To assess the risk gene effects in a cohort consisting of ∼1300 Finnish AD patients and controls, 21 candidate gene polymorphisms were selected for genotyping on the basis of the meta-analyses retrieved from the AlzGene database. A significant genotype and allele association with AD was observed with rs1800629 in the tumor necrosis factor α (TNF). Risk analysis revealed a protective effect for the minor allele carriers of rs1800629. This suggests that genetic alteration in TNF gene may play a role in AD.

Keywords: Alzheimer's disease, inflammation, polymorphism, risk gene, TNF

DOI: 10.3233/JAD-2010-100597

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 763-767, 2010

Authors: Oh, Esther S. | Mielke, Michelle M. | Rosenberg, Paul B. | Jain, Alka | Fedarko, Neal S. | Lyketsos, Constantine G. | Mehta, Pankaj D.

Article Type: Short Communication

Abstract: Plasma amyloid-β (Aβ) level could be useful as a non-invasive biomarker in Alzheimer's disease research. We compared a multiplex electrochemiluminescence detection method with a well established ELISA method for plasma Aβ quantification. Compared to the ELISA method, the electrochemiluminescence detection method demonstrates a statistically significant, but modest correlation. The reasons for this may include the differences in the affinities of antibodies, and purity and source of Aβ peptides used as standards. However, the advantages of electrochemiluminescence detection technology include short processing time and small sample volume. This comparison demonstrates the need for a further study in optimizing this system.

Keywords: Amyloid-β protein, biological markers, enzyme-linked immunosorbent assay, plasma

DOI: 10.3233/JAD-2010-100456

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 769-773, 2010

Authors: Koshy, Beena | Miyashita, Akinori | St. Jean, Pamela | Stirnadel, Heide | Kaise, Toshihiko | Rubio, Justin P. | Mooser, Vincent | Kuwano, Ryozo | Irizarry, Michael C.

Article Type: Short Communication

Abstract: High plasma lipoprotein phospholipase A2 activity (Lp-PLA2 ) is reported to be a risk factor for dementia. A loss of function polymorphism in the Lp-PLA2 gene – PLA2G7 V279F – is found almost exclusively in Asians. In 1,952 subjects with late-onset AD and 2,079 non-demented controls recruited from Japan, the PLA2G7 null allele was not associated with risk or age at onset of AD: logistic regression OR 0.98 (95% CI 0.86–1.12, p = 0.81) per additional null allele, adjusted for age/age at onset, gender, and APOE ε4. Genetic deficiency of Lp-PLA2 activity is not associated with a …reduced risk of AD in the Japanese population. Show more

Keywords: Alzheimer's disease, apolipoprotein E, genetic association study, lipoprotein-associated phospholipase A2, Mendelian randomization

DOI: 10.3233/JAD-2010-100513

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 775-780, 2010

Authors: Nelson, Omar | Supnet, Charlene | Liu, Huarui | Bezprozvanny, Ilya

Article Type: Research Article

Abstract: Mutations in presenilins 1 and 2 (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer's disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid-β protein precursor (AβPP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+ ) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that …most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the “functional” mutations for ER Ca2+ leak were clustered in the exon 8–9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the “functional” and “non-functional” PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD. Show more

Keywords: Alzheimer's disease, amyloid-β, calcium, cotton wool plaques, endoplasmic reticulum, lymphoblasts, presenilins, spastic paraparesis

DOI: 10.3233/JAD-2010-100159

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 781-793, 2010

Authors: Proctor, Dustin T. | Coulson, Elizabeth J. | Dodd, Peter R.

Article Type: Research Article

Abstract: N-methyl-D-aspartate (NMDA) receptor-evoked excitotoxicity contributes to region-specific loss of glutamatergic synapses responsible for cognitive decline in Alzheimer's disease (AD). Here, the post-synaptic scaffold proteins PSD-95 and SAP-102, which regulate NMDA receptor synaptic activity and expression, were investigated in human AD autopsy brain tissue. Using absolute quantification real-time PCR, we detected reduced expression of synaptophysin in both the pathologically susceptible inferior temporal cortex and hippocampus, consistent with previous reports. PSD-95 and SAP-102 mRNA was reduced, albeit not significantly. Proteins were precisely quantified against recombinant truncated protein standards. No differences were observed for proteins in AD spared occipital cortex between AD cases …and controls. PSD-95 and SAP-102 protein expression was markedly reduced in the AD inferior temporal cortex. Both mRNA and protein levels were reduced according to disease severity. SAP102 protein levels were significantly reduced in AD subjects carrying a copy of the APOEε4 allele. This is the first study to investigate SAP-102 in the aging human brain and suggest a possible mechanism for NMDA receptor expression aberrations in AD. Show more

Keywords: Cytoskeletal scaffold, excitotoxicity, glutamate receptors, neurodegeneration, post-synaptic density, signaling

DOI: 10.3233/JAD-2010-100090

Citation: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 795-811, 2010