Volume 18, Number 1, September 2009

Pages 1-9
Review Article

Thibaud Lebouvier, Timothy M.E. Scales, Ritchie Williamson, Wendy Noble, Charles Duyckaerts, Diane P. Hanger, C. Hugh Reynolds, Brian H. Anderton, Pascal Derkinderen
The Microtubule-Associated Protein Tau is Also Phosphorylated on Tyrosine
Abstract: Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer’s disease (AD), where it is hyperphosphorylated on serine and threonine residues. It is hypothesized that this hyperphosphorylation contributes to neurodegeneration through the destabilization of microtubules. There is now evidence that phosphorylation of tau can also occur on tyrosine residues. Human tau has five tyrosines numbered 18, 29, 197, 310, and 394, according to the sequence of the longest CNS isoform. Tyrosines 18, 197, and 394 have been shown to be phosphorylated in the brain of patients with AD whereas tyrosine 394 is the only residue that has been described to date that is phosphorylated in physiological conditions. Src family kinases and spleen tyrosine kinase (Syk) have been shown to phosphorylate tyrosine 18 while c-Abl is capable of phosphorylating tyrosine 394. Recently, a dual specificity kinase termed TTBK1 has been characterized in human brain and shown to be able to phosphorylate residue 197 of tau. Data about the role of tau tyrosine phosphorylation in neuronal physiology are still scarce and preliminary. In contrast, there is mounting evidence suggesting that tau tyrosine phosphorylation is an early event in the pathophysiology of AD and that Fyn and c-Abl are critical in the neurodegenerative process which occurs in tauopathies.

Pages 11-30
Review Article

Roberto Monastero, Francesca Mangialasche, Cecilia Camarda, Sara Ercolani, Rosolino Camarda (Communicated by Patrizia Mecocci)
A Systematic Review of Neuropsychiatric Symptoms in Mild Cognitive Impairment
Abstract: Mild cognitive impairment (MCI) is a clinical concept proposed as an intermediate state between normal aging and dementia. This condition has multiple heterogeneous sources, including clinical presentation, etiology, and prognosis. Recently, the prevalence and associated features of neuropsychiatric symptoms (NPS) in MCI have been described. We systematically searched the PudMed database (last accessed on August 31, 2008) for articles on NPS in MCI. Included articles used strict selection criteria, and outcome variables were extracted in duplicate; of the 27 articles included, 14 (52%) used prospective cohorts. The global prevalence of NPS in MCI ranged from 35% to 85%. The most common behavioral symptoms were depression, anxiety, and irritability. Hospital-based samples reported a higher global prevalence of NPS than population-based studies; this discrepancy probably reflected differences in demographics, study setting, MCI diagnostic criteria, and behavioral instruments used. Prospective studies showed that NPS, particularly depression, may represent risk factors for MCI or predictors for the conversion of MCI to Alzheimer’s disease (AD). NPS are very prevalent in subjects with MCI, displaying a similar pattern of symptoms compared to dementia and AD. Large cohort studies using standardized MCI criteria and behavioral instruments are required to evaluate the prognostic role of NPS in MCI.

Pages 31-33
Short Communication

Ashok K. Dubey, Prashant R. Bharadwaj, Joseph N. Varghese, Ian G. Macreadie
Alzheimer’s Amyloid-β Rescues Yeast from Hydroxide Toxicity
Abstract: Amyloid-β (Aβ42), which is known to be toxic to neuronal cells, protects yeast cells from severe sodium hydroxide toxicity. More than 85% cell death was caused by treatment with 1 mM NaOH and approximately 95% was observed at a 2 mM concentration. However, greater than 55% cells survived the treatment in the presence of Aβ42. A strong protective effect of the peptide was also evident from the differential staining of the treated culture with propidium iodide.

Pages 35-50
Richard C. Davis, Michael T. Maloney, Laurie S. Minamide, Kevin C. Flynn, Matthew A. Stonebraker, James R. Bamburg
Mapping Cofilin-Actin Rods in Stressed Hippocampal Slices and the Role of cdc42 in Amyloid-β-Induced Rods
Abstract: Dissociated hippocampal neurons exposed to a variety of degenerative stimuli form neuritic cofilin-actin rods. Here we report on stimulus driven regional rod formation in organotypic hippocampal slices. Ultrastructural analysis of rods formed in slices demonstrates mitochondria and vesicles become entrapped within some rods. We developed a template for combining and mapping data from multiple slices, enabling statistical analysis for the identification of vulnerable sub-regions. Amyloid-β (Aβ) induces rods predominantly in the dentate gyrus region, and Aβ-induced rods are reversible following washout. Rods that persist 24 h following transient (30 min) ATP-depletion are broadly distributed, whereas rods formed in response to excitotoxic glutamate localize within and nearby the pyramidal neurons. Time-lapse imaging of cofilin-GFP-expressing neurons within slices shows neuronal rod formation begins rapidly and peaks by 10 min of anoxia. In ~50% of responding neurons, Aβ-induced rod formation acts via cdc42, an upstream regulator of cofilin. These new observations support a role for cofilin-actin rods in stress-induced disruption of cargo transport and synaptic function within hippocampal neurons and suggest both cdc42-depedent and independent pathways modulate cofilin activity downstream from Aβ.

Pages 51-64
Fan Liu, M. Arfan Ikram, A Cecile JW. Janssens, Maaike Schuur, Inge de Koning, Aaron Isaacs, Maksim Struchalin, Andre G. Uitterlinden, Johan T. den Dunnen, Kristel Sleegers, Karolien Bettens, Christine Van Broeckhoven, John van Swieten, Albert Hofman, Ben A. Oostra, Yurii S. Aulchenko, Monique M. B. Breteler, Cornelia M. van Duijn (Communicated by Maire Percy)
A Study of the SORL1 Gene in Alzheimer’s Disease and Cognitive Function
Abstract: Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer’s disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD.

Pages 65-70
Anna Aresi and Anna Rita Giovagnoli
The Role of Neuropsychology in Distinguishing the Posterior Cortical Atrophy Syndrome and Alzheimer’s Disease
Abstract: This study investigated the neuropsychological hallmarks of posterior cortical atrophy (PCA). Seventeen patients with PCA, 17 patients with probable Alzheimer’s disease (PAD), and 17 healthy age-matched subjects underwent neuropsychological testing for abstract reasoning, visuospatial abilities, memory, language, executive functions, praxes, and attention. The PCA patients were significantly more impaired in visual perception, spatial memory, visual attention, and visuospatial reasoning compared to the PAD patients who were relatively more impaired in episodic memory. In the PCA group, no test score correlated with disease duration or age of clinical onset, whereas, in the PAD group, several scores correlated with disease duration. Compared to the healthy subjects, both patient groups showed multiple cognitive deficits. Thus, PCA is characterized by distinctive visuospatial deficits that reflect the distribution of brain damage and contrast with the memory impairment of PAD patients. Specific neuropsychological tests may contribute to early identification of cortical dementia for diagnostic and research purposes.

Pages 71-78
Johan Sundelöf, Lena Kilander, Johanna Helmersson, Anders Larsson, Elina Rönnemaa, Malin Degerman-Gunnarsson, Per Sjögren, Hans Basun, Lars Lannfelt, Samar Basu
Systemic Tocopherols and F2-Isoprostanes and the Risk of Alzheimer’s Disease and Dementia: A Prospective Population-Based Study
Abstract: Oxidative stress in the brain is suggested to be involved in the pathophysiology of Alzheimer’s disease (AD). In this study, serum α- and γ-tocopherol, the two major systemic antioxidants, were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n=616 and age 77, n=761). In addition, urinary F2-isoprostane levels, as markers of systemic oxidative stress, were analyzed at the age of 77 in this cohort (n=679). Cox regression analyses were used to examine associations between serum α-, γ-tocopherol and urinary F2-isoprostane levels and AD, any type of dementia (all-cause dementia) and non-AD dementia. On follow-up (median, 12.3 years), 40 subjects developed AD and 86 subjects developed all-cause dementia. Serum α- and γ-tocopherol or urinary F2-isoprostane levels were not associated with the future risk of AD or dementia. In conclusion, systemic serum α- and γ-tocopherol and urinary F2-isoprostane levels are not associated with the future risk of AD or dementia and do not seem to be useful predictors of clinical AD or dementia.

Pages 79-87
Johan Sundelöf, Lena Kilander, Johanna Helmersson, Anders Larsson, Elina Rönnemaa, Malin Degerman-Gunnarsson, Hans Basun, Lars Lannfelt, Samar Basu
Systemic Inflammation and the Risk of Alzheimer’s Disease and Dementia: A Prospective Population-Based Study
Abstract: Inflammation is suggested to be involved in the pathogenesis of Alzheimer’s disease (AD). Serum interleukin-6 (IL-6) and high sensitivity serum reactive protein C (hsCRP) as markers of systemic inflammation were analyzed at two examinations of the ULSAM-study, a longitudinal, community-based study of elderly men (age 70, n=1062 and age 77, n=749). In addition, serum amyloid protein A (SAA) and urinary prostaglandin F2α (PGF2α) metabolite levels were analyzed at age 77 in this cohort. Two serial samples (at ages 70 and 77) were available from 704 individuals. Using Cox regression analyses, associations between serum IL-6, hsCRP, SAA and PGF2α metabolite levels and risk of AD, any type of dementia (all-cause dementia) and non-AD dementia were analyzed. On follow-up (median, 11.3 years) in the age 70 cohort, 81 subjects developed AD and 165 subjects developed all-cause dementia. Serum IL-6, hsCRP, SAA, or PGF2α levels were not associated with risk of AD. At age 70, high IL-6 levels were associated with an increased risk of non-AD dementia (Hazard ratio 2.21 for above vs. below/at median, 95% confidence interval 1.23-3.95, p-value=.008). A longitudinal change in CRP or IL-6 levels was not associated with AD or dementia. In conclusion, Serum IL-6, hsCRP, SAA, and PGF2α levels are not associated with the risk of AD. High serum IL-6 levels may be associated with increased risk of non-AD dementia.

Pages 89-102
Bin Zhou, Satoshi Teramukai, Kenichi Yoshimura, Masanori Fukushima
Validity of Cerebrospinal Fluid Biomarkers as Endpoints in Early-Phase Clinical Trials for Alzheimer’s Disease
Abstract: A systematic literature review was performed to assess the suitability of cerebrospinal fluid (CSF) levels of protein amyloid-β42 (Aβ42) and tau as markers to detect the disease-modifying effects of drugs in clinical trials of AD treatments. All databases were searched for observational studies, single-arm clinical trials, and randomized controlled trials involving patients with AD in which CSF Aβ42 and tau were measured. A meta-analytic random-effects model was used to evaluate the mean absolute change in protein concentration over time. Spearman correlation was used to assess the association between change in CSF protein concentration and change in cognitive function. The mean changes per month in observational studies were -0.4 pg/ml/month (95% CI: -1.9 to 1.1) for 8 CSF Aβ42 and 1.5 pg/ml/month (95% CI: 0.1 to 3.0) for 12 CSF tau studies. The correlation coefficients for the relationship between CSF protein concentration and cognition were 0.43 (p=0.068) for all 18 Aβ42 studies and -0.05 (p=0.857) for all 18 tau studies. A trend in which CSF Aβ42 decreases and tau protein increases over time was identified in AD patients. CSF Aβ42 and tau concentrations should be used with caution as surrogate endpoints in early-phase clinical trials for AD.

Pages 103-104
Commentary on Zhou et al.

   Joseph Quinn, Christoper M. Clark
   Failure of Biomarkers in Clinical Trials of Alzheimer's Disease: Blaming the Messenger?

Pages 105-111
Lina Ji, Abha Chauhan, Jerzy Wegiel, Musthfa M. Essa, Ved Chauhan
Gelsolin is Proteolytically Cleaved in the Brains of Individuals with Alzheimer’s Disease
Abstract: Gelsolin, a multifunctional actin-binding protein, forms a complex with amyloid-β protein and reduces the amyloid load in the transgenic mouse model of Alzheimer’s disease (AD). Gelsolin consists of six homologous domains, which have specific affinities for phosphatidylinositol 4, 5-bisphosphate, calcium, and actin. During apoptosis, gelsolin is cleaved by the caspase-3 resulting in a 48 kDa carboxyl-terminal fragment (gelsolin-CTF). We report here that gelsolin is significantly cleaved in the frontal cortex of individuals with AD as compared to age-matched controls. A positive correlation was observed between the appearance of gelsolin-CTF in frontal cortex and severity of AD. Gelsolin-CTF was also observed in apoptotic SH-SY5Y cells induced by H2O2 or calcium ionophore A23187. In addition, lipid peroxidation was increased in the frontal cortex of AD suggesting that oxidative stress occurs in AD brain. Taken together, these results suggest that there may be a link among oxidative stress, neuronal apoptosis, and gelsolin cleavage in AD.

Pages 113-124
Mario G. Ferruzzi, Jessica K. Lobo, Elsa M. Janle, Naomi Whittaker, Bruce Cooper, James E. Simon, Qing-Li Wu, Cara Welch, Lap Ho, Connie Weaver, Giulio M. Pasinetti
Bioavailability of Gallic Acid and Catechins from Grape Seed Polyphenol Extract is Improved by Repeated Dosing in Rats: Implications for Treatment in Alzheimer’s Disease
Abstract: The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer’s disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3’-methytlcatechin (3’-OMeC), and 3’-methylepicatechin (3’-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 ± 45.9 and 576.7 ± 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

Pages 125-130
Diego Albani, Francesca Prato, Mauro Tettamanti, Carlo Lovati, Daniela Galimberti, Ilaria Restelli, Claudio Mariani, Pier Luigi Quadri, Elio Scarpini, Ugo Lucca, Gianluigi Forloni (Communicated by Alessandro Serretti)
The Serotonin Transporter Promoter Polymorphic Region is not a Risk Factor for Alzheimer’s Disease Related Behavioral Disturbances
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and often accompanied during its progression by behavioral and psychological symptoms of dementia (BPSD). We decided to evaluate the association between AD-related behavioral disturbances and the short/long (S/L) polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). This functional polymorphism modulates SLC6A4 transcription rate, with the S-allele having a 2-fold reduced efficiency, leading to a diminished availability of 5-HT that might in turn trigger behavioral and cognitive alterations. The SLC6A4 promoter functional single nucleotide polymorphism rs25531 (AàG) was genotyped as well. We collected 235 sporadic AD subjects that were classified as AD with (n=122) or without (n=113) behavioral alterations, assessed with the Spontaneous Behavior Interview scale, section Behavioral Problems (SBI-BP). Comparing the genotypic and allelic frequencies of AD without and with BPSD, we did not find a difference for the 5-HTTLPR or the rs25531, even after stratification according to single SBI-BP item. We conclude that 5-HTTLPR and rs25531 are not major genetic modulators of BPSD development in AD.

Pages 131-139
Yitshak I Francis*, Mauro Fà*, Haider Ashraf, Hong Zhang, Agnieszka  Staniszewski, David S. Latchman, Ottavio Arancio (Communicated by Luciano D’Adamio) *These authors have contributed equally to the studies presented in this manuscript.
Dysregulation of Histone Acetylation in the APP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Epigenetic mechanisms such as post-translational histone modifications are increasingly recognized for their contribution to gene activation and silencing in the brain. Histone acetylation in particular has been shown to be important both in hippocampal long-term potentiation (LTP) and memory formation in mice. The involvement of the epigenetic modulation of memory formation has also been proposed in neuropathological models, although up to now no clear-cut connection has been demonstrated between histone modifications and the etiology of Alzheimer’s disease (AD). Thus, we have undertaken preclinical studies in the APP/PS1 mouse model of AD to determine whether there are differences in histone acetylation levels during associative memory formation. After fear conditioning training, levels of hippocampal acetylated histone 4 (H4) in APP/PS1 mice were about 50% lower than in wild-type littermates. Interestingly, acute treatment with a histone deacetylase inhibitor, Trichostatin A (TSA), prior to training rescued both acetylated H4 levels and contextual freezing performance to wild-type values. Moreover, TSA rescued CA3-CA1 LTP in slices from APP/PS1 mice. Based on this evidence, we propose the hypothesis that epigenetic mechanisms are involved in the altered synaptic function and memory associated with AD. In this respect, histone deacetylase inhibitors represent a new therapeutic target to effectively counteract disease progression.

Pages 141-151
Alejandro Barrantes, Javier Sotres, Mercedes Hernando-Pérez, Maria J. Benítez, Pedro J. de Pablo, Arturo M. Baró, Jesus Ávila, Juan S. Jiménez
Tau Aggregation Followed by Atomic Force Microscopy and Surface Plasmon Resonance, and Single Molecule Tau-Tau Interaction Probed by Atomic Force Spectroscopy
Abstract: Intracellular neurofibrillary tangles, composed mainly of tau protein, and extracellular plaques, containing mostly amyloid-β, are the two types of protein aggregates found upon autopsy within the brain of Alzheimer’s disease patients. Polymers of tau protein can also be found in other neurodegenerative disorders known as tauopathies. Tau is a highly soluble protein, intrinsically devoid of secondary or tertiary structure, as many others proteins particularly prone to form fibrillar aggregations. The mechanism by which this unfolded molecule evolves to the well ordered helical filaments has been amply studied. In fact, it is a very slow process when followed in the absence of aggregation inducers. Herein we describe the use of surface plasmon resonance, atomic force microscopy, and atomic force spectroscopy to detect tau-tau interactions and to follow the process of aggregation in the absence of aggregation inducers. Tau-tau interactions are clearly detected, although a very long period of time is needed to observe filaments formation. Tau oligomers showing a granular appearance, however, are observed immediately as a consequence of this interaction. These granular tau oligomers slowly evolve to larger structures and eventually to filaments having a size smaller than those reported for paired helical filaments purified from Alzheimer’s disease.

Pages 153-165
Yan Hou, Young-Beob Yu, Gengtao Liu, Yuan Luo
A Natural Squamosamide Derivative FLZ Reduces Amyloid-β Production by Increasing Non-Amyloidogenic AβPP Processing
Abstract: Substantial evidence supports a central role of Aβ in the pathogenesis of Alzheimer’s disease (AD). We have demonstrated that FLZ, a synthetic cyclic analogue of natural squamosamide, exhibits neuroprotective actions in cells and mouse models, suggesting future investigation of FLZ as a candidate compound for the treatment of AD. In this study, we found that production of amyloid-β (Aβ) was reduced by FLZ in Aβ-expressing neuroblastoma cells, which correlates with an increase in the soluble α-secretase derived fragment of the amyloid-β protein precursor (sAβPPα) in the medium. Moreover, the active form of ADAM10 and AβPP were elevated at the cell surface of FLZ-treated cells, consistent with an enhanced co-localization of ADAM10 and AβPP on the membrane. Pretreatment with brefeldin, a protein trafficking inhibitor, blocked FLZ-induced translocation of ADAM10 to the cell surface and release of sAβPPα to the culture medium. Furthermore, oral administration of FLZ to APPswe/PS1 transgenic mice significantly reduced the levels of Aβ, parallel with activation of ADAM10, in the hippocampus. In silico prediction indicates that the structure of FLZ agree with the drug-like rules for absorption and permeability. These findings suggest that reducing Aβ production by FLZ may be mediated by its promotion of AβPP non-amyloidogenic α-secretase processing, and FLZ has therapeutic potential for the treatment of AD.

Pages 167-176
Guozhang Mao, Jianxin Tan, Mei-Zhen Cui, Dehua Chui, Xuemin Xu
The GxxxG Motif in the Transmembrane Domain of AβPP Plays an Essential Role in the Interaction of CTFβ with the γ-secretase Complex and the Formation of Amyloid-β
Abstract: g-secretase-mediated processing of the amyloid-β protein precursor (AβPP) is a crucial step in the formation of the amyloid-β peptide (Aβ), but little is known about how the substrate AβPP interacts with the g-secretase complex. To understand the molecular events involved in g-secretase-mediated AβPP processing and Aβ formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of AβPP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of Aβ. Furthermore, our data revealed that substitution of aspartic acid for the glycine in this GxxxG motif disrupts the interaction of AβPP with the g-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of AβPP with the g-secretase complex and the formation of Aβ.

Pages 177-189
Oliver Peters, Carola G. Schipke, Andreas Philipps, Brigitte Haas, Ulrike Pannasch, Li Ping Wang, Bruno Benedetti, Ann E. Kingston, Helmut Kettenmann
Astrocyte Function is Modified by Alzheimer’s Disease-like Pathology in Aged Mice
Abstract: Alzheimer’s disease (AD) may affect all cell types in the central nervous system. Astrocytes have rarely been investigated in the aged brain and the role of astrocytes in AD is poorly understood. In this study, we used acute brain slices from an amyloid-β overexpressing double transgenic mouse line where astrocytes express the enhanced green fluorescent protein under the control of the glial fibrillary acidic protein promoter. Using the patch-clamp technique, we analyzed cell coupling and glutamate reactivity, two main features of astrocytes, in the living tissue of aged mice in an AD mouse model. We found large astrocytic networks in the aged (20 to 27 months) transgenic animals in the neocortex, but not in the hippocampus. In contrast, coupling was low in all brain regions of aged control mice. We furthermore noticed significant changes in the responses of astrocytes to glutamate. The expression of functional glutamate transporters and AMPA/kainate-type glutamate receptors increases in the amyloid-β protein precursor overexpressing mice. Thus, exposure to amyloid-β leads to altered astrocyte properties and this change might be beneficial to maintain synaptic function.

Pages 191-199
Alberto Pilotto, Daniele Sancarlo, Francesco Panza, Francesco Paris, Grazia D’Onofrio, Leandro Cascavilla, Filomena Addante, Davide Seripa, Vincenzo Solfrizzi, Bruno Dallapiccola, Marilisa Franceschi, Luigi Ferrucci
The Multidimensional Prognostic Index (MPI) Based on a Comprehensive Geriatric Assessment Predicts Short- and Long-Term Mortality in Hospitalized Older Patients with Dementia
Abstract: Aim of this study was to evaluate the usefulness of a Multidimensional Prognostic Index (MPI) based on a Comprehensive Geriatric Assessment (CGA) for predicting mortality risk in older patients with dementia. The present was a retrospective study with a year of follow-up that included 262 patients aged 65 years and older with a diagnosis of dementia. A standardized CGA that included information on clinical, cognitive, functional, and nutritional aspects, as well as comorbidity, medications, and social support network, was used to calculate MPI. The predictive value of the MPI for all-cause mortality over 1 month, 6 months, and 12 months of follow-up was evaluated. Higher MPI values were significantly associated with higher mortality at 1 month (MPI-1, low risk=0%, MPI-2, moderate risk=5.2%, MPI-3, severe risk=13.7%; p<0.002), 6-months (MPI-1=2.7%, MPI-2=11.2%, MPI-3=28.8%; p<0.001), and 12-months (MPI-1=2.7%, MPI-2=18.2%, MPI-3=35.6%; p<0.001) of follow-up. The discrimination of the MPI was also good, with areas under the ROC curves of 0.77 (sensitivity=82.9%, specificity=66.0%, with a cut off value > 0.16) at 12-months of follow up. In conclusion, the MPI, calculated from information collected in a standardized CGA, accurately stratified hospitalized elderly patients with dementia into groups at varying risk of short- and long-term mortality.

Pages 201-210
Claudius Mueller, Shino Magaki, Matthew Schrag, Manik C. Ghosh, Wolff M. Kirsch (Communicated by Othman Ghribi)
Iron Regulatory Protein 2 is Involved in Brain Copper Homeostasis
Abstract: Trace metal homeostasis is tightly controlled in the brain, as even a slight dysregulation may severely impact normal brain function. This is especially apparent in Alzheimer’s disease, where brain homeostasis of trace metals such as copper and iron is dysregulated. As it is known that iron and copper metabolism are linked, we wanted to investigate if a common mechanism could explain the increase in iron and decrease in copper seen in Alzheimer’s disease brain. Amyloid-β protein precursor (AβPP) has been implicated in copper efflux from the brain. Furthermore, it was shown that iron regulatory proteins (IRP), which regulate iron homeostasis, can block AβPP mRNA translation. In a correlative study we have therefore compared brain regional copper levels and AβPP expression in mice with a targeted deletion of IRP2-/-. Compared with controls, six week old IRP2-/- mice had significantly less brain copper in the parietal cortex, hippocampus, ventral striatum, thalamus, hypothalamus, and whole brain, while AβPP was significantly upregulated in the hippocampus (p<0.05) and showed a trend toward upregulation in the thalamus (p<0.1). This is the first study to demonstrate that iron regulatory proteins affect brain copper levels, which has significant implications for neurodegenerative diseases.

Pages 211-230
Remi Dosunmu, Jinfang Wu, Lina Adwan, Bryan Maloney, Md. Riyaz Basha, Christopher A. McPherson, G. Jean Harry, Deborah C. Rice, Nasser H. Zawia, Debomoy K. Lahiri
Lifespan Profiles of Alzheimer’s Disease-Associated Genes and Their Products in Monkeys and Mice
Abstract: Alzheimer’s disease (AD) is characterized by plaques of amyloid–β (Aβ) peptide, cleaved from amyloid-β protein precursor (AβPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AβPP mRNA, AβPP protein, and Aβ levels in rodents and primates. We also tracked a transcriptional regulator of the AβPP gene, specificity protein 1 (SP1), and the β amyloid precursor cleaving enzyme (BACE1). In mice, AβPP and SP1 mRNA and their protein products were elevated late in life; Aβ levels declined in old age. In monkeys, SP1, AβPP, and BACE1 mRNA declined in old age, while protein products and Aβ levels rose. Proteolytic processing in both species did not match production of Aβ. In primates, AβPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Aβ levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases.

Pages 231-232
Book Review:
Animal Models of Human Cognitive Aging, Jennifer L. Bizon and Alisa G. Woods (Eds.), Humana Press, a part of Springer Science + Business Media, LLC, New York, 2009, 208 pp. Reviewed by Gemma Casadesus.

Pages 233-239
Meeting Report from the Alzheimer Research Forum
Human Amyloid Imaging, Seattle, Washington, 24 April 2009