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

Authors: Roher, Alex E. | Maarouf, Chera L. | Daugs, Ian D. | Kokjohn, Tyler A. | Hunter, Jesse M. | Sabbagh, Marwan N. | Beach, Thomas G.

Article Type: Research Article

Abstract: The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-β (Aβ) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Aβ profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed …that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy. The Aβ species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length Aβ1-42 and truncated Aβ peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment. Show more

Keywords: Active immunotherapy, Alzheimer's disease, amyloid-β, amyloid plaques, bapineuzumab, cerebral amyloid angiopathy, neurofibrillary tangles, passive immunotherapy

DOI: 10.3233/JAD-2011-101809

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 315-325, 2011

Authors: Smith, Edward R. | Nilforooshan, Ramin | Weaving, Gary | Tabet, Naji

Article Type: Research Article

Abstract: The significance of vascular risk factors in the development and progression of Alzheimer's disease (AD) is now widely recognized. Fetuin-A is an abundant plasma protein that predicts vascular risk in a variety of clinical settings. In the context of cerebral ischemia, fetuin-A appears to be anti-inflammatory. Given the apparent importance of neuroinflammation in cognitive decline, we analyzed fetuin-A concentrations and pro-inflammatory cytokine levels in a cohort of 34 patients with mild-to-moderate AD, and compared these to age-matched controls. Further, we analyzed the relationship between plasma fetuin-A concentration and a measure of cognitive impairment using multivariate regression modeling. Plasma fetuin-A concentrations …were lower in the patient group (p = 0.006) compared with controls and were significantly correlated with Mini-Mental State Examination (MMSE) score (r = 0.504, p = 0.002). Fetuin-A concentration was also significantly and inversely correlated with plasma TNF-α concentration (r = −0.496, p = 0.003). The association between MMSE performance and fetuin-A was maintained even after multivariate adjustment for other risk factors including TNF-α (adjusted R2 total = 0.371). Using this model, plasma fetuin-A concentration explained 21% of the variance in MMSE scores. Further studies are needed to evaluate whether fetuin-A is related to the progression and pathogenesis of AD. Show more

Keywords: Alpha2HS glycoprotein, Alzheimer's disease, inflammation, tumor necrosis factor-alpha

DOI: 10.3233/JAD-2011-101872

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 327-333, 2011

Authors: Prà, Ilaria Dal | Whitfileld, James F. | Pacchiana, Raffaella | Bonafini, Clara | Talacchi, Andrea | Chakravarthy, Balu | Armato, Ubaldo | Chiarini, Anna

Article Type: Research Article

Abstract: Astrocytes in amyloid-β (Aβ)42 -accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with Aβ42 . We have already shown that Aβ25-35 (surrogate of Aβ42 )-induced VEGF-A production in ‘normoxic’ cultures of early passage normal human cerebral astrocytes (NAHAs) is mediated by the stabilization of VEGF gene-stimulating hypoxia-inducible factor (HIF)-1α and nuclear translocation of HIF-1α•HIF-1β complexes. We have now found that treating these NAHAs with Aβ25-35 also stimulates them to make Aβ42 (appearing in immunoblots as several bands with Mr 's from 8 kDa upwards), whose levels …peak at 48 h (2.8-fold versus 0 h, p < 0.001) and then start falling slowly. This rise of Aβ42 peptide production coincides with a transiently increased flow of HIF-1α (therefore HIF-1α•HIF-1β complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of β-secretase (BACE-1/β-S) mRNA expression (1.2-fold versus 0 h, p = 0.013) and activity peaking at 24-h (1.4-fold versus 0 h, p = 0.001), and then of γ-secretase (γ-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the Aβ42 peptides from amyloid-β protein precursor. Since the genes encoding components of these two secretases have the same HIF-1α•HIF-1β-responsive elements in their promoters as the VEGF gene, these observations suggest that the Aβ42 released from neurons in the AD brain can recruit associated astrocytes via HIF-1α•HIF-1β signaling into the pool of Aβ42 -producing cells. In other words, Aβ42 begets Aβ42 in NAHAs. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, β-secretase/BACE-1, γ-secretase, HIF, normal adult human astrocytes

DOI: 10.3233/JAD-2011-101626

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 335-347, 2011

Authors: Chigurupati, Srinivasulu | Madan, Meenu | Okun, Eitan | Wei, Zelan | Pattisapu, Jogi V. | Mughal, Mohamed R. | Mattson, Mark P. | Chan, Sic L.

Article Type: Research Article

Abstract: The cell fate determinant Numb exists in four alternatively spliced variants that differ in the length of their PTB (phosphotyrosine-binding domain, either lacking or containing an 11 amino acid insertion) and PRR (proline-rich region, either lacking or containing a 48 amino acid insertion). We previously reported that Numb switches from isoforms containing the PTB insertion to isoforms lacking this insertion in neural cultures subjected to stress induced by trophic factor withdrawal. The switch in Numb isoforms enhances the generation of amyloid-β peptide (Aβ), the principle component of senile plaques in Alzheimer's disease (AD). Here we examine the expression of the …Numb isoforms in brains from AD patients and triple transgenic (3xTg) AD mice. We found that levels of the Numb isoforms lacking the PTB insertion are significantly elevated in the parietal cortex but not in the cerebellum of AD patients when compared to control subjects. Levels of Numb isoforms lacking the PTB insertion were also elevated in the cortex but not cerebellum of 12 month-old 3xTg AD mice with Aβ deposits compared to younger 3xTg-AD mice and to non-transgenic mice. Exposure of cultured neurons to Aβ resulted in an increase in the levels of Numb isoforms lacking the PTB domain, consistent with a role for Aβ in the aberrant expression of Numb in vulnerable brain regions of AD patients and mice. Collectively, the data show that altered expression of Numb isoforms in vulnerable neurons occurs during AD pathogenesis and suggest a role for Numb in the disease process. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, endocytosis, endosomes, protein trafficking

DOI: 10.3233/JAD-2011-101797

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 349-361, 2011

Authors: Frölich, Lutz | Ashwood, Tim | Nilsson, Jonas | Eckerwall, Göran | on behalf of the Sirocco Investigators

Article Type: Research Article

Abstract: AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12–26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21–26). Mean age was 74 (range 58–85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at …Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25–26) indicated improvement versus placebo for AZD3480 20 mg (−1.4, 95% CI: −3.0; 0.2) and donepezil (−1.0, 95% CI: −2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients. Show more

Keywords: Alzheimer's disease, AZD3480, cognitive impairment, NNR agonist, randomized controlled trial

DOI: 10.3233/JAD-2011-101554

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 363-374, 2011

Authors: Railey, Angela M. | Groeber, Caitlin M. | Flinn, Jane M.

Article Type: Research Article

Abstract: The amyloid-β protein (Aβ) is a metalloprotein with affinity for the metal ions zinc (Zn), copper (Cu), and iron (Fe), which are found in high concentrations in the plaques of Alzheimer's disease (AD). Increasing attention is focused on the role of these metals in AD, and much of the evidence suggests a dyshomeostasis between these metal ions may significantly affect Aβ aggregation and deposition in the brain. While the effect of these metals on Aβ has been shown in vitro, there is less behavioral data supporting a direct role in cognitive impairment. In order to investigate the cognitive consequences of …metal dyshomeostasis, we sought to directly increase metal levels in the brain by dietary means in a transgenic mouse model (Tg2576). We have now examined the effect of increased Zn (10 ppm) and Fe (10 ppm) levels in the drinking water in the Tg2576 mouse. Since increased dietary Zn can lead to Cu deficiency, a Zn group supplemented with copper was also examined (Zn (10 ppm)+Cu (0.025 ppm)). Significant increases in latency and fewer platform crossings on probe trials, which are considered measures of spatial memory impairment, were seen in both Fe and Zn supplemented transgenic mice, compared to those raised on lab water. No significant differences were seen between the Zn + Cu group and in transgenic mice raised on lab water. These data suggest that the negative consequences of Zn may be due to a reduction in copper levels and, therefore, an imbalance between these metal ions rather than a direct effect of increased Zn. Show more

Keywords: Alzheimer's disease, copper, iron, maze learning, metal ions, spatial memory disorder, transgenic mice, zinc

DOI: 10.3233/JAD-2011-101452

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 375-381, 2011

Authors: Mollenhauer, Brit | Esselmann, Herrmann | Trenkwalder, Claudia | Schulz-Schaeffer, Walter | Kretzschmar, Hans | Otto, Markus | Wiltfang, Jens | Bibl, Mirko

Article Type: Research Article

Abstract: Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid-β (Aβ) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Aβ peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Aβ-SDS-PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities …of CSF Aβ-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Aβ-peptides (Aβ1-X% . Aβ1-42% was lowered in dAD compared to NDC (p = 1.6 × 10−7 , but did not differ between dAD and pAD. Aβ1-40ox% was elevated in dDLB as compared to NDC (p = 1.8 × 10−5 , but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Aβ peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Aβ1-42% and Aβ1-40ox% as diagnostic biomarkers for AD and DLB, respectively. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid, dementia with Lewy bodies, neuropathologically confirmed diagnosis

DOI: 10.3233/JAD-2011-101551

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 383-391, 2011

Authors: Kim, SangYun | Park, Moon Ho | Han, Seol-Heui | Na, Hae Ri | Cho, SungJin | Choi, Mun Seong | Lee, Jae-Hong | Na, Duk L. | Kim, Jung Eun | Park, Kun Woo

Article Type: Research Article

Abstract: Screening tests that briefly measure early signs of cognitive dysfunction in Alzheimer's disease (AD) are lacking. We devised a new scale focused on early detecting cognitive dysfunction: the Attention Questionnaire Scale (AQS). We prospectively studied the AQS in 268 subjects with varying degrees of cognitive dysfunction and compared it with the Mini-Mental Status Examination (MMSE), digit span test, trail making test part B, letter cancellation test, Instrumental ADL, Geriatric Depression Scale, and Clinical Dementia Rating Scale. The internal consistency was excellent with the AQS (Cronbach's α = 0.945). There were significant differences in the overall AQS scores across varying degree …of cognitive dysfunction (26.80 ± 3.43 in normal elderly, 20.78 ± 4.83 in patients with mild cognitive impairment (MCI), 19.01 ± 4.49 in early AD, 16.00 ± 5.03 in mild AD, and 12.02 ± 6.28 in moderate AD), and subjects with the early stage of cognitive dysfunction could be further distinguished using the AQS than MMSE. The area under the receiver operating characteristic curve was estimated to be 0.93 (95% confidence interval 0.89–0.97) in screening for normal elderly versus patients with MCI or various stages of AD. The AQS provides greater screening ability for early stage cognitive dysfunction, used not only as a screening tool but also an appropriate simple questionnaire. Show more

Keywords: Alzheimer's disease, attention, dementia, questionnaire

DOI: 10.3233/JAD-2011-100660

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 393-402, 2011

Authors: Small, David H.

Article Type: Book Review

DOI: 10.3233/JAD-2010-110004

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 403-404, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-101552

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 405-407, 2011