Volume 7, Number 4, August 2005

Pages 267-272
J.F. Collingwood, A. Mikhaylova, M. Davidson, C. Batich, W.J. Streit, J. Terry, J. Dobson
In situ Characterization and Mapping of Iron Compounds in Alzheimer’s Disease Tissue
Abstract: There is a well-established link between iron overload in the brain and pathology associated with neurodegeneration in a variety of disorders such as Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases. This association was first discovered in AD by Goodman in 1953, where, in addition to abnormally high concentrations of iron in autopsy brain tissue, iron has also been shown to accumulate at sites of brain pathology such as senile plaques. However, since this discovery, progress in understanding the origin, role and nature of iron compounds associated with neurodegeneration has been slow. Here we report, for the first time, the location and characterisation of iron compounds in human AD brain tissue sections. Iron fluorescence was mapped over a frontal-lobe tissue section from an Alzheimer’s patient, and anomalous iron concentrations were identified using synchrotron X-ray absorption techniques at 5µm spatial resolution. Concentrations of ferritin and magnetite, a magnetic iron oxide potentially indicating disrupted brain-iron metabolism, were evident. These results demonstrate a practical means of correlating iron compounds and disease pathology in-situ and have clear implications for disease pathogenesis and potential therapies.

Pages 273-284
Erzsébet Andrási, Noémi Páli, Zsuzsa Molnár, Siegfried Kösel (Communicated by Sharon Moalem)
Brain Al, Mg and P contents of control and Alzheimer-diseased patients
Abstract: A study was undertaken to determine Al, Mg and P concentrations in 5 different brain regions of 3 control and 3 Alzheimer-diseased patients. One of the aims of this work was to evaluate the performance of applied analytical techniques. The digested samples were analyzed by inductively coupled plasma atomic emission spectrometry for Al, Mg and P. The dried samples were measured by instrumental neutron activation analysis for Al and Mg. The determination of human brain Al levels is complicated by the interfering reaction of P. We have previously worked out an analytical method which can eliminate this interference. The accuracy of the measured data was investigated by the analysis of biological standard reference materials. Our second goal was to study the possible elemental concentration changes in Alzheimer-diseased patients. Significantly higher Al and lower Mg and P values were found in some AD brain regions compared to the controls.

Pages 285-289
Marwan N. Sabbagh, Ann Marie Hake, Sahir Ahmed, Martin R. Farlow
The Use of Memantine in Dementia with Lewy Bodies
Abstract: OBJECTIVE: To determine the effect of memantine in the treatment of Dementia with Lewy Bodies (DLB). BACKGROUND: While memantine has been used to successfully treat moderate-to-severe Alzheimer’s disease and some non AD dementias, no reports are available regarding the effect of the drug on DLB. METHODS: We reviewed the charts of 11 subjects with DLB by McKeith Criteria that were prospectively evaluated and treated with memantine (with or without cholinesterase inhibitors (ChEIs)) for varying lengths of time. RESULTS: 9 of 11 DLB subjects on memantine were also on ChEIs. Seven of eleven were stable or improved with memantine while the remaining four worsened or responded adversely when exposed to the drug. No adverse effects on motor function were observed. CONCLUSIONS: Memantine can be used safely in patients with DLB, but its symptomatic effects may be variable.

Pages 291-295
Roberto Monastero, Cecilia Camarda, Angelo B. Cefalù, Rosalia Caldarella, Lawrence K.C. Camarda, Davide Noto, Maurizio R. Averna, Rosolino Camarda (Communicated by Patrizia Mecocci)
No Association Between the Cystatin C Gene Polymorphism and Alzheimer's Disease: a Case-Control Study in an Italian Population
Abstract: Cystatin C is an amyloidogenic protein found together with beta-amyloid in cerebral arteriolar walls of both patients with Alzheimer's Disease (AD) and conghopilic amyloid angiopathy. Several findings implicate cystatin C in the pathogenesis of vascular diseases. Recent genetic association studies proposed cystatin C gene (CST3) as a susceptibility factor for AD, although other reports did not replicate this finding. We conducted a case-control study including 192 probable AD cases and 192 age- and sex-matched controls to test the association between CST3 and AD. Possible interaction between CST3 and age at onset of AD or apolipoprotein E (APOE) was also examined. No significant differences in CST3 genotype or allele frequencies between cases and controls was observed, while the risk of AD increased in subjects carrying the APOE epsilon4 allele (OR 3.5, 95% CI [2.1-5.9]). There was no interaction between CST3 with age or APOE. Our findings do not support a role of CST3 gene in Italian sporadic AD.

Pages 297-301
Thomas B. Shea, Daniela Ortiz, Robert J. Nicolosi, Rajesh Kumar, Arthur C. Watterson
Nanosphere-mediated delivery of vitamin E increases its efficacy against oxidative stress resulting from exposure to amyloid beta
Abstract: Oxidative stress is an early hallmark of affected neurons in Alzheimer's disease (AD). The antioxidant vitamin E provided limited neuroprotection in AD, which may have derived from its lipophilic nature and resultant inability to quench cytosolic reactive oxygen species (ROS), including those generated from antecedent membrane oxidative damage. We examined herein whether or not encapsulation into polyethylene glycol (PEG)-based nanospheres, which can enter the cytosol, improved the efficacy of vitamin E against Aß-induced ROS. Unexcapsulated vitamin E prevented Aß-induced ROS in cultured SH-SY-5Y human neuroblastoma cells only if present prior to, or applied simultaneously with, Aß treatment. By contrast, encapsulated vitamin E was equally effective if administered 1hr after Aß exposure. These findings suggest suggests that nanosphere-mediated delivery methods may be a useful adjunct for antioxidant therapy in AD.

Pages 303-314
Hone E., Martins I.J., Jeoung M., Ji T.H., Gandy S.E., Martins R.N. (Communicated by Ved Chauhan)
Alzheimer's disease amyloid-beta peptide modulates apolipoprotein E isoform specific receptor binding.
Abstract: The major protein component of the extracellular deposits in Alzheimer's disease (AD) is a 4 kDa peptide termed amyloid-ß (Aß). This peptide is known to bind apolipoprotein E (apoE), a key mediator of lipoprotein transport, in an isoform specific manner. Whilst these isoform specific effects on apoE are well recognized, the functional significance of this interaction is poorly understood. Here, we investigated the influence of Aß on apoE-mediated lipoprotein binding to cells using fluorescently tagged lipoprotein-like emulsions. Using this approach, we demonstrate that Aß enhanced the normally poor binding of apoE2 lipoprotein-like particles to fibroblasts in culture, whilst markedly reducing the binding of apoE3 and apoE4. This suggests that the action of apoE isoforms on cellular lipoprotein or cholesterol metabolism is differentially modulated by Aß. This also suggests that Aß may also compromise apoE function in the Alzheimer disease affected brain.

Commentary on the Hone et al. manuscript:

Pages 315-317
A. Bierhaus, P. P. Nawroth
Posttranslational modification of lipoproteins – a fatal attraction in metabolic disease?

Pages 319-324
Todd A. Lee, Benjamin Wolozin, Kevin B. Weiss, Martin M. Bednar (Communicated by Craig Atwood)
Assessment of the Emergence of Alzheimer's Disease Following Coronary Artery Bypass Graft Surgery or Percutaneous Transluminal Coronary Angioplasty
Abstract: Post-Operative Cognitive Decline (POCD) is a complication of Coronary Artery Bypass Graft (CABG) surgery and is consistent with reduced neuronal reserve. We performed a retrospective cohort analysis of Veterans Affairs (VA) patients undergoing CABG or PTCA between October 1, 1996 and September 30, 1997 to examine if CABG surgery is associated with the earlier emergence of cognitive impairment such as Alzheimer's Disease (AD). The emergence of dementia following CABG surgery was compared to dementia in a cardiac population undergoing percutaneous transluminal coronary angioplasty (PTCA). Patients were followed from the date of their procedure until September 30, 2002, the diagnosis of Alzheimer's disease or death. Cox proportional hazards models were used to compare the risk of AD development. Patients analyzed were ³ 55 yrs old without baseline dementia. The results show that a total of 119 patients (CABG = 78; PTCA = 41) developed AD during the follow-up period. The adjusted risk of AD associated with CABG versus PTCA was 1.71 (95% CI, 1.02 to 2.87; p= 0.04). These results suggest that patients undergoing CABG surgery were at increased risk for the emergence of AD than those undergoing PTCA. These data support the hypothesis that CABG surgery is associated with a reduced neuronal reserve in an aging population.

Pages 325-330
N.T. Lautenschlager, Jing-Shan Wu, S.M. Laws, O.P. Almeida, R.M. Clarnette, K. Joesbury, S. Wagenpfeil, G. Martins, A.Paton, S.E. Gandy, H. Förstl, R.N. Martins
Neurological soft signs are associated with APOE genotype, age and cognitive performance
Abstract: Neurodegeneration is associated with increased frequency of neurological soft signs (NSS). We designed the present study to investigate the association between NSS and subjective memory complaints, cognitive function and apolipoprotein E genotype in a community-dwelling sample of volunteers participating in an ongoing longitudinal program investigating predictors of cognitive decline. NSS were found to be associated with apolipoprotein E (APOE) e 4 genotype (p=0.015), age (p=0.012) and poor cognitive performance, as assessed by the Mini Mental State Examination (p=0.053). There was no significant difference between subjects with and without memory complaints in relation to the frequency of NSS (p=0.130). The association with age and the APOE e 4 genotype suggests that the systematic investigation of NSS may contribute to identify subjects at risk of clinically significant cognitive decline in later life.

Pages 331-353
Alessandro Serretti, Paola Artioli, Roberto Quartesan, Diana De Ronchi (Communicated by Patrizia Mecocci)
Genes involved in AD, a survey of possible candidates
Abstract: Alzheimer's disease (AD) is the major cause of dementia in the elderly. It is characterized by a progressive deterioration in memory and cognitive functions, but also behavioral symptoms are common. Many different genes are possibly involved in Alzheimer's disease: four genetic factors were confirmed in different studies, while at least 50 additional genes were tested with contrasting results. A major aim both for clinician and researchers would be the identification of the genes involved in AD, to better understand the biological mechanism of this disease and consequently to develop appropriate treatments. The aim of this review is to explore genetics of AD.

Pages 355-360
Transcript: Alzheimer Research Forum Live Discussion
The Pathogen Hypothesis

Page 361
Book Review: Neurological and Psychiatric Disorders: From Bench to Bedside, by Frank I. Tarazi and John A. Schetz, Humana Press, Inc., Totowa, New Jersey, February 2005, 280 pp. Reviewed by Dr. Alexandre Valério de Mendonça.