Journal of Alzheimer's Disease - Volume 24, issue 2

Authors: Avidan, Michael S. | Evers, Alex S.

Article Type: Review Article

Abstract: A strong perception exists that elderly people are at risk for persistent cognitive deterioration lasting longer than six months following major surgery, particularly heart surgery. Furthermore, based on laboratory evidence, investigators hypothesize that surgery or anesthesia might precipitate incident dementia. Recent clinical studies have found that cognition might frequently be impaired within the first few months postoperatively, and that such impairment may be associated with death or debility. Unsurprisingly, the specter of cognitive decline or dementia following surgery is a source of consternation to elderly people and their families. However, there are methodological concerns relating to the investigation of postoperative …cognitive decline. Studies have been hampered by lack of standard diagnostic criteria for cognitive decline, by the use of statistical rather than clinical definitions, by poorly matched controls or even the absence of controls, and by inadequate detection of preexisting mild dementia. For these reasons, there are ongoing controversies surrounding the time course, the severity, and even the clinical relevance of persistent postoperative cognitive deterioration. There is evidence that most patients recover cognition in the long-term, and that for those who experience persistent decline, this is probably attributable to underlying undiagnosed neurological disease or other co-morbidities rather than to surgery or to anesthesia. There is currently minimal clinical evidence linking surgery or anesthesia to incident dementia. Rigorous clinical research is needed to resolve the controversy whether anesthesia or surgery is likely to cause persistent neurological decline or to precipitate dementia. Show more

Keywords: Alzheimer's disease, cognitive, cognitive disorders, cognitive impairment, dementia, postoperative, postoperative cognitive decline (POCD), postoperative complications

DOI: 10.3233/JAD-2011-101680

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 201-216, 2011

Authors: Sanders, Robert D.

Article Type: Article Commentary

DOI: 10.3233/JAD-2011-101681

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 217-220, 2011

Authors: Aboukhatwa, Marwa | Luo, Yuan

Article Type: Research Article

Abstract: It is estimated that 30%–50% of Alzheimer's disease (AD) patients are diagnosed with major or minor depression. Research that addresses the relationship between these two diseases will benefit patients who suffer from depression comorbid with AD and allow further understanding of the neuroanatomy of depression. A clinical study showed that the use of the antidepressant fluoxetin concomitantly with the FDA-approved AD drug rivastigmine provided an improvement in the daily activities and the overall functioning in the patients with cognitive impairment. In an attempt to understand the underlying mechanism for the antidepressant's beneficial effect in AD patients, we evaluated the effects …of different classes of antidepressants on the amyloid-β peptide (Aβ) species in N2a neuroblastoma cells overexpressing amyloid-β protein precursor. The effect of increasing antidepressant concentrations on the intracellular and secreted Aβ species is investigated by Western blotting. The tested antidepressants include fluoxetine, paroxetine, maprotiline, and imipramine. Fluoxetine and paroxetine at 10 μM significantly decreased the intracellular level of Aβ oligomers and increased the level of Aβ monomers. However, imipramine and maprotiline increased the intracellular amount of Aβ monomers without affecting Aβ oligomers. Based on these results, it is possible that fluoxetine and paroxetine could be beneficial to AD patients via reducing the level of the cytotoxic oligomers and keeping the Aβ peptide in the monomeric form. These data could explain some of the beneficial effects of antidepressants in AD patients observed in clinical studies. Show more

Keywords: Alzheimer's disease, amyloid beta toxicity, antidepressant drugs, cell model

DOI: 10.3233/JAD-2011-101113

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 221-234, 2011

Authors: Lescai, Francesco | Chiamenti, Andrea Maria | Codemo, Alessandra | Pirazzini, Chiara | D'Agostino, Giuseppe | Ruaro, Cristina | Ghidoni, Roberta | Benussi, Luisa | Galimberti, Daniela | Esposito, Federica | Marchegiani, Francesca | Cardelli, Maurizio | Olivieri, Fabiola | Nacmias, Benedetta | Sorbi, Sandro | Tagliavini, Fabrizio | Albani, Diego | Boneschi, Filippo Martinelli | Binetti, Giuliano | Santoro, Aurelia | Forloni, Gianluigi | Scarpini, Elio | Crepaldi, Gaetano | Gabelli, Carlo | Franceschi, Claudio

Article Type: Research Article

Abstract: This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the ε4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (−491 rs449647, −427 rs769446, −219 rs405509, and ε rs429358–rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants −219T and ε4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in …phase); 2) the correlation between the haplotype (−219T/ε4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between −219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified. Show more

Keywords: Alzheimer disease, apolipoprotein E, genetics, polymorphism, single nucleotide

DOI: 10.3233/JAD-2011-101764

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 235-245, 2011

Authors: Lutz, Michael W. | Crenshaw, Donna G. | Saunders, Ann M. | Roses, Allen D.

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-101765

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 247-251, 2011

Authors: Pietroboni, Anna M. | Fumagalli, Giorgio G. | Ghezzi, Laura | Fenoglio, Chiara | Cortini, Francesca | Serpente, Maria | Cantoni, Claudia | Rotondo, Emanuela | Corti, Priscilla | Carecchio, Miryam | Bassi, Mariateresa | Bresolin, Nereo | Galbiati, Domenico | Galimberti, Daniela | Scarpini, Elio

Article Type: Research Article

Abstract: The Asp22fs(g.63_64insC) mutation in progranulin gene (GRN) has been so far reported in one patient who developed frontotemporal dementia (FTD) at the age of 65. Here, we describe the clinical heterogeneity associated with the GRN Asp22fs mutation in a large Italian family. Clinical and instrumental workup of two symptomatic carriers in two generations has been carried out, together with genetic analysis of probands and of nine asymptomatic family members. The first proband was a 47-year old male clinically diagnosed with FTD. Family history was positive and suggestive of an autosomal dominant pattern of inheritance. Evaluation of plasma GRN levels was …consistent with the presence of a mutation in its encoding gene, that was demonstrated by sequencing [Asp22fs(g.63_64insC)]. Brain MRI showed multiple T2 and FLAIR hyperintense areas in the frontal lobe white matter and right hemisphere cortical atrophy. The second proband was his 79 year old uncle, presenting with mild cognitive impairment. Brain MRI showed small T2 hyperintense lesions and widespread cortical atrophy. Cerebrospinal fluid amyloid-β, tau, and phosphotau protein levels were in both cases in the range of normality. Additional nine asymptomatic family members were studied. This family's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by GRN mutations, suggesting that the diagnosis could be missed in some individuals with an atypical presentation, and points up the importance of GRN plasma level evaluation. Show more

Keywords: Alzheimer's disease, frontotemporal lobar degeneration (FTLD), haploinsufficiency, heterogeneity, mutation, phenotype, progranulin, progranulin plasma levels

DOI: 10.3233/JAD-2011-101704

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 253-259, 2011

Authors: Pennington, Catherine | Hodges, John R. | Hornberger, Michael

Article Type: Research Article

Abstract: Impaired episodic memory is currently an exclusion criterion for behavioral variant frontotemporal dementia (bv-FTD), although prior studies have shown that neuropsychological memory performance varies from very impaired to intact in such patients. Our study investigated i) whether this variability might be due to the admixture of true bv-FTD and phenocopy syndrome patients and ii) the neural correlates of episodic memory deficits in bvFTD. Groups of patients with true bvFTD (n = 14), phenocopy syndrome (n = 6), Alzheimer's disease (AD) (n = 14), and healthy controls (n = 15) underwent memory testing and had MRI scanning with ratings of regional …brain atrophy. Phenocopy patients did not differ to controls on memory scores or atrophy ratings. By contrast, bvFTD and AD patients were impaired on both measures in comparison to controls and more importantly, bvFTD and AD did not differ on memory scores. Atrophy patterns differed, with AD showing typical medial temporal lobe atrophy, while bvFTD patients had predominantly prefrontal cortex atrophy. In bvFTD neuropsychological memory performance correlated with frontal atrophy ratings while in AD significant correlations were found between memory and both medial temporal lobe and frontal atrophy ratings. Taken together, out data shows that bvFTD patients can show a similar degree of episodic memory impairment on neuropsychological tests to AD patients, however, the neural correlates differ. The previously variable reported memory performance in bvFTD is likely due to the inclusion of phenocopy patients, who are mostly undistinguishable from controls. These findings have implications for the diagnosis of bvFTD. Show more

Keywords: AD, behavioral variant frontotemporal dementia (bvFTD), episodic memory, MRI, phenocopy syndrome

DOI: 10.3233/JAD-2011-101668

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 261-268, 2011

Authors: Yang, Jing | Ji, Yong | Mehta, Pankaj | Bates, Kristyn A. | Sun, Yanjie | Wisniewski, Thomas

Article Type: Research Article

Abstract: The accumulation of amyloid-β (Aβ) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of Aβ peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. We have shown that blocking the Aβ/ApoE interaction with Aβ12-28P , a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing Aβ parenchymal deposition. In the present study, we investigate this therapeutic effect on CAA in the transgenic (Tg) AD mice model (TgSwDI), which expresses Swedish (K670N/M671L), Dutch …(E693Q)/Iowa (D694N) AβPP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that A12-28P treated TgSwDI AD mice performed the same as wild-type mice, whereas vehicle treated TgSwDI were impaired in spatial memory. Furthermore, this treatment resulted in a significant reduction of total amyloid burden, especially the fibrillar vascular amyloid burden, which importantly was accompanied by a reduction in microhemorrhages and neuroinflammation. Measurement of Aβ levels in the brain homogenate revealed a significant decrease in both the total amount of Aβ and Aβ oligomer levels in A12-28P treated TgSwDI mice. These findings suggest that blocking the Aβ/ApoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, cerebral amyloid angiopathy, microhemorrhages, microglia, neuroinflammation

DOI: 10.3233/JAD-2011-101401

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 269-285, 2011

Authors: Schallier, Anneleen | Smolders, Ilse | Van Dam, Debby | Loyens, Ellen | De Deyn, Peter Paul | Michotte, Alex | Michotte, Yvette | Massie, Ann

Article Type: Research Article

Abstract: Using 8- and 18-month-old AβPP23 mice, we investigated the involvement of high-affinity glutamate transporters (GLAST, GLT-1, EAAC1), vesicular glutamate transporters (VGLUT1-3) and xCT, the specific subunit of system xc − , in Alzheimer's disease (AD) pathogenesis. Transporter expression was studied in cortical and hippocampal tissue and linked to extracellular glutamate and glutamate reuptake activity as measured using in vivo microdialysis. In 8-month-old animals, we could not observe plaque formation or gliosis. Yet, in hippocampus as well as cortex GLAST and GLT-1 expression was decreased. Whereas in cortex this was accompanied by upregulated VGLUT1 expression, extracellular glutamate concentrations were decreased. Surprisingly, …inhibiting glutamate reuptake with TBOA revealed increased glutamate reuptake activity in cortex of AβPP23 mice, despite decreased GLAST and GLT-1 expression, and resulted in status epilepticus in all AβPP23 mice, contrary to wildtype littermates. In hippocampus of 8-month-old AβPP23 mice, we observed increased EAAC1 expression besides the decrease in GLAST and GLT-1. Yet, glutamate reuptake activity was drastically decreased according to the decreased GLAST and GLT-1 expression. In 18-month-old AβPP23 mice, plaque formation and gliosis in cortex and hippocampus were accompanied by decreased GLT-1 expression. We also showed, for the first time, increased cortical expression of VGLUT3 and xCT together with a strong tendency towards increased cortical extracellular glutamate levels. VGLUT2 expression remained unaltered in all conditions. The present findings support the hypothesis that alterations in transport of glutamate, and more particular via GLT-1, may be involved in AD pathogenesis. Show more

Keywords: Alzheimer's disease, AβPP23 model, cortex, EAAT, hippocampus, VGLUT, xCT

DOI: 10.3233/JAD-2011-101005

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 287-300, 2011

Authors: van Groen, Thomas | Miettinen, Pasi | Kadish, Inga

Article Type: Research Article

Abstract: The deposition of amyloid-β (Aβ) peptides in plaques and intracellular neurofibrillary tangles are the two main characteristic pathological features of Alzheimer's disease (AD). Significantly, plaques are surrounded by activated astrocytes, microglia, and possibly, macrophages, and it has been suggested that this activity contributes to the pathology. Whether this will lead to a decrease or an increase in the amount of Aβ deposition is not clear. To investigate the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus and neocortex following three anti-inflammatory treatments aimed at reducing the amyloid burden. In these studies we …treated mice with different non-steroidal anti-inflammatory drugs for several months (i.e., from 8 through 14 months of age), and studied the Aβ pathology and inflammation in the brain. Sham treatment and flurbiprofen treatment did not affect Aβ pathology, and a low dose HCT 1026 (10 mg/kg; a nitric oxide-donating flurbiprofen analog that has additional useful properties, including a remarkable gastrointestinal safety) did not affect pathology either, however a higher dose of HCT 1026 (30 mg/kg) did reduce the Aβ load. Furthermore, this treatment reduced the amount of microglial activation surrounding plaques. In contrast, the low dose of HCT 1026 increased GFAP activation, but did not change microglial activation. Together the data indicate that changing the activity of glial cells can lead to both a decrease of the amyloid burden, and to detrimental changes, likely caused by the interplay between the activation levels of astrocytes and microglial cells. Show more

Keywords: Alzheimer's disease, amyloid deposition, amyloid-β protein precursor, astrocytes, HCT 1026, microglia, transgenic mice

DOI: 10.3233/JAD-2011-101479

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 301-313, 2011