Volume 35, Number 3, May 2013

Pages 427-440
Lidia Glodzik, Catherine Randall, Henry Rusinek, Mony J. de Leon (Handling Associate Editor: Piotr Lewczuk)
Cerebrovascular Reactivity to Carbon Dioxide in Alzheimer’s Disease
Abstract: There is growing evidence that cerebrovascular reactivity to carbon dioxide (CVRCO2) is impaired in Alzheimer’s disease (AD). Preclinical and animal studies suggest chronic hypercontractility in brain vessels in AD. We review (a) preclinical studies of mechanisms for impaired CVRCO2 in AD; (b) clinical studies of cerebrovascular function in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition. Although results of clinical studies are inconclusive, an increasing number of reports reveal an impairment of vascular reactivity to carbon dioxide in subjects with AD, and possibly also in MCI. Thus, CVRCO2 may be an attractive means to detect and treat an early vascular dysfunction in subjects at risk.

Pages 441-450
Norman B. Javitt
Alzheimer’s Disease: Neuroprogesterone, Epoxycholesterol, and ABC Transporters as Determinants of Neurodesmosterol Tissue Levels and its Role in Amyloid Protein Processing 
Abstract: Evidence is emerging that during the development of Alzheimer's disease (AD), changes in the synthesis and metabolism of cholesterol and progesterone are occurring that may or may not affect the progression of the disease. The concept arose from the recognition that dehydrocholesterol 24-reductase (DHCR24/Seladin-1), one of the nine enzymes in the endoplasmic reticulum that determines the transformation of lanosterol to cholesterol, is selectively reduced in late AD. As a consequence, the tissue level of desmosterol increases, affecting the expression of ABC transporters and the structure of lipid rafts, both determinants of amyloid-β processing. However, the former effect is considered beneficial and the latter detrimental to processing. Other determinants of desmosterol tissue levels are 24,25 epoxycholesterol and the ABCG1 and ABCG4 transporters. Progesterone and its metabolites are determinants of tissue levels of desmosterol and several other sterol intermediates in cholesterol synthesis. Animal models indicate marked elevations in the tissue levels of these sterols at early time frames in the progression of neurodegenerative diseases. The low level of neuroprogesterone and metabolites in AD are consonant with the low level of desmosterol and may have a role in amyloid-β processing. The sparse data that has accumulated appears to be a sufficient basis for proposing a systematic evaluation of the biologic roles of sterol intermediates in the slowly progressive neurodegeneration characteristic of AD.

Short Communication
Christian Schmidt, André Karch, Svetlana Artjomova, Martin Hoeschel, Inga Zerr
Pre-Progression Rates in Alzheimer’s Disease Revisited 
Abstract: Background: Pre-progression rates (PPR) in Alzheimer’s disease (AD) have been reported to be associated with cognitive and functional decline. Objective: The objective was to reevaluate PPRs in a prospective cohort of AD patients. Methods: A prospective AD cohort was analyzed. Multiple regression was used to examine associations of PPRs with short term decline on different cognitive and functional scales (MMSE, instrumental and basic ADL, GDS, UPDRS III). Results: PPRs were only associated with first year instrumental ADL declines.Conclusion: The predictive abilities of PPRs could partially be confirmed. These findings can help to adapt patient care shortly after diagnosis.

Pages 455-462
Chiara Cerami, Alessandra Marcone, Daniela Galimberti, Michele Zamboni, Chiara Fenoglio, Maria Serpente, Elio Scarpini, Stefano F. Cappa
Novel Evidence of Phenotypical Variability in the Hexanucleotide Repeat Expansion in Chromosome 9 
Abstract: C9ORF72 repeat expansion is currently considered as a major genetic cause of amyotrophic lateral sclerosis (ALS) and, in particular, of combined frontotemporal dementia-motor neuron disorder (FTD-MND) pedigrees. Studies of large series of patients have indicated that various phenotypic presentations may be observed even in the same family. Here, we describe four patients carrying a C9ORF72 mutation with heterogeneous clinical presentation sharing a rapid disease course. Cases #1 and #2 presented with predominant semantic deficits, accompanied in one patient by clinical signs of ALS. Case #3 showed a phenotype compatible with a diagnosis of behavioral variant of FTD. Case #4 presented with memory impairments, apathy, and social withdrawal, and had negative cerebrospinal fluid markers for Alzheimer’s disease. Two patients showed a positive familiar history of MND and dementia (at least one first-degree family member affected). The two other patients were apparently sporadic cases. Our data provide further evidence for the heterogeneity of phenotypes associated with the C9ORF72 mutation and indicate its association with a fluent progressive aphasia phenotype. The present findings confirm the importance of screening for the hexanucleotide repeat expansion in chromosome 9 in the case not only of familial, but also of sporadic FTD, and in the presence of atypical cognitive disorders.

Pages 463-473
Maria Paz Zurita, Gonzalo Muñoz, Fernando J. Sepúlveda, Paulina Gómez, Carolina Castillo, Carlos F. Burgos, Jorge Fuentealba, Carlos Opazo, Luis G. Aguayo
Ibuprofen Inhibits the Synaptic Failure Induced by the Amyloid-β Peptide in Hippocampal Neurons 
Abstract: Epidemiological studies have reported a decrease in the prevalence of Alzheimer’s disease in individuals who chronically use non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials, on the other hand, have been less positive. Nevertheless, it has been proposed that NSAIDs exert part of their effects by reducing long-term cerebral neuroinflammation, although this mechanism has not been proven. In this study, we report that ibuprofen, one of the more widely used non-steroidal anti-inflammatory drugs, was able to alter the ultrastructure of amyloid-β peptide (Aβ) and significantly decrease its association to neuronal membranes, and consequently, its synaptotoxic effect in rat primary hippocampal and cortical cultures at 24 h incubation. In agreement with these results, we found that the decrease in the frequency of calcium transients with Aβ was partly recovered by addition of ibuprofen (8.0x10-2 Hz in control; 3.4x10-2 Hz in 5 μM Aβ, and 5.9x10-2 Hz in presence of Aβ and 200 μM ibuprofen). Additionally, this effect correlated well with the increment and recovery of miniature spontaneous currents (47±5% of control in 1 μM Aβ alone and 104±14% in presence of Aβ and ibuprofen). Our results suggest that ibuprofen could be exerting its neuroprotective effect by directly interacting with Aβ and altering its toxic aggregated forms. We postulate that other ibuprofen analogs with better pharmacological properties might have a higher efficacy in AD.

Pages 475-486
Surabhi Bhatia, Andrew M. Jenner, Hongyun Li, Kalani Ruberu, Adena S. Spiro, Claire E. Shepherd, Jillian J. Kril, Nupur Kain, Anthony Don, Brett Garner
Increased Apolipoprotein D Dimer Formation in Alzheimer’s Disease Hippocampus is Associated with Lipid Conjugated Diene Levels
Abstract: Previous studies indicate that apolipoprotein D (apoD) may have a lipid antioxidant function in the brain. We have shown that apoD can reduce free radical-generating lipid hydroperoxides to inert lipid hydroxides in a reaction that involves conversion of surface exposed apoD methione-93 (Met93) residue to Met93-sulfoxide (Met93-SO). One consequence of this reaction is the formation of a stable dimerized form of apoD. As cerebral lipid peroxidation is associated with Alzheimer’s disease (AD), in the present study we aimed to assess the possible presence of apoD dimers in postmortem hippocampal and cerebellar tissues derived from a cohort of pathologically defined cases ranging from control to late stage AD. Both soluble and insoluble (requiring guanidine HCl extraction) fractions of tissue homogenates were analyzed for apoD and its dimerized form. We also assessed amyloid-β levels by ELISA and levels of lipid peroxidation by lipid conjugated diene and F2-isoprostane analysis. Our studies reveal a significant association between soluble apoD levels and AD Braak stage whereas apoD dimer formation appears to increase predominantly in the advanced stages of disease. The formation of apoD dimers is closely correlated to lipid conjugated diene levels and occurs in the hippocampus but not in the cerebellum. These results are consistent with the hypothesis that apoD acts as a lipid antioxidant in the brain.

Pages 487-494
Chiara Villa, Elisa Ridolfi, Chiara Fenoglio, Laura Ghezzi, Roberto Vimercati, Francesca Clerici, Alessandra Marcone, Salvatore Gallone, Maria Serpente, Claudia Cantoni, Rossana Bonsi, Sara Cioffi, Stefano Cappa, Massimo Franceschi, Innocenzo Rainero, Claudio Mariani, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Benedetta Nacmias)
Expression of the Transcription Factor Sp1 and its Regulatory hsa-miR-29b in Peripheral Blood Mononuclear Cells from Patients with Alzheimer’s Disease
Abstract: Altered gene expression occurs in central nervous system disorders, including Alzheimer’s disease (AD). Transcription factor Sp1 (specificity protein 1) can regulate the expression of several AD-related proteins, including amyloid-β protein precursor and tau. Sp1 is regulated by oxidative stress, and Sp1 mRNA was found to be upregulated in AD cortex and hippocampus. The distribution of three single nucleotide polymorphisms (SNPs), including rs7300593, rs17695156, and rs12821290, covering 100% Sp1 genetic variability, has been determined in a population of 393 AD patients as compared with 412 controls. In addition, expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR-375) has been performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. No differences in all three SNP distributions were observed in AD patients as compared with controls. Stratifying according to gender, a significantly decreased frequency ofSp1 rs17695156 T allele was observed in male patients versus male controls. Significantly increased Sp1 relative expression levels were observed in PBMCs from AD patients as compared with controls. Western blot analysis paralleled mRNA increase in AD patients versus controls and correlated positively with Sp1 mRNA levels. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients versus controls and correlated negatively with Sp1 mRNA levels. According to these results,Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. Moreover, Sp1rs176951056 T allele is likely a protective factor in the male population.

Pages 495-507
Alberto Fernández, Agustín Turrero, Pilar Zuluaga, Pedro Gil-Gregorio, Francisco del Pozo, Fernando Maestu, Stephan Moratti (Handling Associate Editor: Ricardo Bajo)
MEG Delta Mapping along the Healthy Aging-Alzheimer’s Disease Continuum: Diagnostic Implications
Abstract: New diagnostic criteria for Alzheimer’s disease (AD) stress the role of in vivobiomarkers. Neurophysiological markers are usually not considered as such criteria, although theoretical and practical reasons would justify them. In order to assess the value of neurophysiology as an AD biomarker, whole-head magnetoencephalographic (MEG) resting state recordings were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The AD group was further split into two groups differing in severity according to the GDS/FAST criteria. A Minimum Norm Estimation procedure was utilized to estimate the cortical origin of slow brain oscillatory activity in the delta band (2-4Hz).Eight regions of interest (ROIs) discriminated between AD patients and controls. Delta current density (DCD) in all ROIs showed a significant negative correlation with cognitive status (p<0.001). DCD values in posterior parietal, occipital, prerolandic, and precuneus cortices distinguished reliably between MCI patients, AD patients with different severity scores, and controls. Importantly, an increase of DCD in right parietal cortex and precuneus indexed the transition from MCI to mild dementia and from mild to more severe dementia. MEG delta mapping might be a serious candidate for a “neural degeneration” marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in line with functional imaging markers of AD. However, MEG delta mapping is a totally non-invasive technique that directly measures neural activity. We propose that individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full dementia.

Pages 509-524
Lisa Mosconi, Randolph D. Andrews, Dawn C. Matthews and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (Handling Associate Editor: Benedetta Nacmias)
Comparing Brain Amyloid Deposition, Glucose Metabolism, and Atrophy in Mild Cognitive Impairment with and without a Family History of Dementia 
Abstract: This study compares the degree of brain amyloid-β (Aβ) deposition, glucose metabolism, and grey matter volume (GMV) reductions in mild cognitive impairment (MCI) patients overall and as a function of their parental history of dementia. Ten MCI with maternal history (MH), 8 with paternal history (PH), and 24 with negative family history (NH) received 11C-PiB and 18F-FDG PET and T1-MRI as part of the Alzheimer’s Disease Neuroimaging Initiative. Statistical parametric mapping, voxel based morphometry, and Z-score mapping were used to compare biomarkers across MCI groups, and relative to 12 normal controls. MCI had higher PiB retention, hypometabolism, and GMV reductions in Alzheimer-vulnerable regions compared to controls. Biomarker abnormalities were more pronounced in MCI with MH than those with PH and NH. After partial volume correction of PET, Aβ load exceeded hypometabolism and atrophy with regard to the number of regions affected and magnitude of impairment in those regions. Hypometabolism exceeded atrophy in all MCI groups and exceeded Aβ load in medial temporal and posterior cingulate regions of MCI MH. While all three biomarkers were abnormal in MCI compared to controls, Aβ deposition was the most prominent abnormality, with MCI MH having the greatest degree of co-occurring hypometabolism.

Supplementary Data for Mosconi et al. article (PDF)

Pages 525-539
Maria J. Casarejos*, Juan Perucho*, Ana Gomez, Maria P. Muñoz, Marian Fernandez-Estevez, Onintza Sagredo, Javier Fernandez Ruiz, Manuel Guzman, Justo Garcia de Yebenes, Maria A. Mena *These authors contributed equally to this work. 
Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy
Abstract: Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress,s and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders.

Supplementary Data for Casarejos et al. article (PDF)

Pages 541-552
Ajay Singh, Swati Haldar, Katharine Horback, Cynthia Tom, Lan Zhou, Howard Meyerson,Neena Singh
Prion Protein Regulates Iron Transport by Functioning as a Ferrireductase 
Abstract: Prion protein (PrPC) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP-/-). When exposed to non-transferrin-bound (NTB) radioactive-iron (59FeCl3) by gastric-gavage, PrP-/- mice absorb significantly more 59Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP+/+) controls that remain iron over-loaded, PrP-/- mice revert back to the iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP-/- mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP-/- BM-macrophages incorporate significantly less NTB-59Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrPC. When expressed in neuroblastoma cells, PrPC exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-59Fe by neuroblastoma cells correlates with FR activity of PrPC, implicating PrPC in cellular iron uptake and metabolism. These observations explain the correlation between PrPC expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrPC accumulates as insoluble aggregates.

Supplementary Data for Singh et al. article (PDF)

Pages 553-564
Marie-France Nissou, Jacques Brocard, Michèle El Atifi, Audrey Guttin, Annie Andrieux, François Berger, Jean-Paul Issartel, Didier Wion
The Transcriptomic Response of Mixed Neuron-Glial Cell Cultures to 1,25-Dihydroxyvitamin D3 includes Genes Limiting the Progression of Neurodegenerative Diseases
Abstract: Seasonal or chronic vitamin D deficiency and/or insufficiency is highly prevalent in the human population. Receptors for 1,25-dihydroxyvitamin D3, the hormonal metabolite of vitamin D, are found throughout the brain. To provide further information on the role of this hormone on brain function, we analyzed the transcriptomic profiles of mixed neuron-glial cell cultures in response to 1,25-dihydroxyvitamin D3. 1,25-dihydroxyvitamin D3 treatment increases the mRNA levels of 27 genes by at least 1.9 fold. Among them, 17 genes were related to neurodegenerative and psychiatric diseases, or brain morphogenesis. Notably, 10 of these genes encode proteins potentially limiting the progression of Alzheimer’s disease. These data provide support for a role of 1,25-dihydroxyvitamin D3 in brain disease prevention. The possible consequences of circannual or chronic vitamin D insufficiencies on a tissue with a low regenerative potential such as the brain should be considered.

Supplementary Data for Nissou et al. article (PDF)

Pages 565-573
Patrick Imfeld, Yolanda B. Brauchli Pernus, Susan S. Jick, Christoph R. Meier
Epidemiology, Co-Morbidities, and Medication Use of Patients with Alzheimer’s Disease or Vascular Dementia in the UK
Abstract: Epidemiologic studies on age-specific incidence rates (IRs) separating Alzheimer’s disease (AD) and vascular dementia (VaD) in the UK are scarce. We sought to assess IRs of AD and VaD in the UK and to compare co-morbidities and medication use between patients with AD, VaD, or without dementia. We identified cases aged ≥65 years with an incident diagnosis of AD or VaD between 1998 and 2008 using the General Practice Research Database (GPRD). We assessed IRs, stratified by age and gender, matched one dementia-free control patient to each demented patient, and analyzed co-morbidities and medication use. We identified 7,086 AD and 4,438 VaD cases. Overall, the IR of AD was 1.59/1,000 person-years (py) (95% CI 1.55–1.62) and the IR of VaD 0.99/1,000 py (95% CI 0.96–1.02). For AD, IRs were higher for women than for men, but not for VaD. Except for orthostatic hypotension, the prevalence of all cardiovascular (CV) co-morbidities and exposure to CV drugs was lower in patients with AD than in corresponding controls, whereas the opposite was true for VaD. The lower prevalence of CV diseases in patients with AD may be a true finding or the result of a channeling effect, i.e., the possibility that demented patients with CV diseases may be more likely diagnosed with VaD than AD.

Supplementary Data for Imfeld et al. article (PDF)

Pages 575-587
Franka Thurm, Daria Antonenko, Winfried Schlee, Stephan Kolassa, Thomas Elbert, Iris-Tatjana Kolassa
Effects of Aging and Mild Cognitive Impairment on Electrophysiological Correlates of Performance Monitoring 
Abstract: Performance monitoring tasks are suitable for investigating aging-related decline in executive functions. However, little is known about performance monitoring in premature pathological aging and mild cognitive impairment (MCI). This study recorded the error-related negativity (ERN) and the correct-related negativity (CRN) as indices of performance monitoring and compared these responses in older adults with MCI to the ones of younger and older adult controls. No differences in either ERN or CRN were found between younger and older adult controls. Compared to both control groups, we observed a more negatively pronounced CRN in MCI subjects. Only in this group did the amplitude of the CRN not differ from the one of the ERN. In general, larger differences between both components (i.e., ERN > CRN) were associated with better performances in cognitive tests requiring inhibition and executive control. These results indicate that electrophysiological correlates of performance monitoring (ERN and CRN) are differentially affected by aging and MCI.

Supplementary Data for Thurm et al. article (PDF)

Pages 589-597
Ana Navarro, Eva del Valle, Eva Mártínez, Cristina Ordóñez, Cristina Pérez, Jorge Tolivia
Highly Selective and Fast Diagnosis of Alzheimer's Disease Hallmark Lesions using Congo Red in Isopropyl Alcoholic Solution
Abstract: A highly selective, rapid, inexpensive, simple, and immunocytochemical compatible fluorescence staining method for Alzheimer’s disease hallmark lesions applicable to sections of human specimens embedded in paraffin is described. Human necropsy material was fixed in buffered formalin, sectioned at 10 μm, mounted on slides, deparaffinized, and partially hydrated (70% ethanol). After partial hydration, sections were stained for 10 min in a solution of 0.2% Congo red in 70% isopropanol. After washing in 70% isopropanol and rehydration, auto-fluorescence of sections were quenched (optional) and processed for immunocytochemistry (optional). Finally, sections were mounted in an adequate mounting medium. Amyloid deposits appear pink at light microscopy and all Alzheimer’s disease hallmark lesions appear orange or red under fluorescence microscopy using blue or green exciting light, respectively. The present method can be used in combination with all pre- or post-immunocytochemical techniques.

Pages 599-609
Stephen W. Scheff, Douglas A. Price, Frederick A. Schmitt, Kelly N. Roberts, Milos D. Ikonomovic, Elliott J. Mufson (Handling Associate Editor: Thomas Beach)
Synapse Stability in the Precuneus Early in the Progression of Alzheimer’s Disease
Abstract: Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer’s disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the p rogression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD.

Pages 611-621
Line Roed, Gisle Grave, Torbjørn Lindahl, Edith Rian, Peter O. Horndalsveen, Lars Lannfelt, Christer Nilsson, Frank Swenson, Anders Lönneborg, Praveen Sharma, Magnus Sjögren(Handling Associate Editor: Brit Mollenhauer) 
Prediction of Mild Cognitive Impairment that Evolves into Alzheimer’s Disease Dementia within Two Years using a Gene Expression Signature in Blood: A Pilot Study
Abstract: Background: The focus on Alzheimer’s disease (AD) is shifting from dementia to the prodromal stage of the disorder, to a large extent due to increasing efforts in trying to develop disease modifying treatment for the disorder. For development of disease-modifying drugs, a reliable and accurate test for identification of mild cognitive impairment (MCI) due to AD is essential. Objective: In the present study, MCI progressing to AD will be predicted using blood-based gene expression. Material and Methods: Gene expression analysis using qPCR was performed on blood RNA from a cohort of patients with amnestic MCI (aMCI; n=66). Within the aMCI cohort, patients progressing to AD within 1 to 2 years were grouped as MCI converters (n=34) and the patients remaining at in the MCI stage after 2 years were grouped as stable MCI (n=32). AD and control populations were also included in the study. Results:Multivariate statistical method partial least square regression was used to develop predictive models which later were tested using leave-one-out cross validation. Gene expression signatures that identified aMCI subjects that progressed to AD within 2 years with a prediction accuracy of 74%-77% were identified for the complete dataset and subsets thereof.Conclusion: The present pilot study demonstrates for the first time that MCI that evolves into AD dementia within 2 years may be predicted by analyzing gene expression in blood. Further studies will be needed to validate this gene signature as a potential test for AD in the predementia stage.

Pages 623-635
Cristina Carvalho, Nuno Machado, Paula C. Mota, Sónia C. Correia, Susana Cardoso, Renato X. Santos, Maria S. Santos, Catarina R. Oliveira, Paula I. Moreira 
Type 2 Diabetic and Alzheimer’s Disease Mice Present Similar Behavioral, Cognitive, and Vascular Anomalies
Abstract: Type 2 diabetes (T2D) is considered a major risk factor for Alzheimer’s disease (AD). To elucidate the links between both pathological conditions, we compared behavioral and cognitive functions, cerebral amyloid-β peptide (Aβ) levels and vasculature integrity of 11-month-old T2D and AD mice. For this purpose, we performed behavioral tests (open field, object recognition, Y-maze, and elevated plus maze tests), ELISA to assess plasma markers of endothelial/vascular dysfunction, spectrophotometric assays to evaluate cerebral vascular permeability and enzymatic activities, and immunohistochemistry for the assessment of Aβ levels. Both T2D and AD showed similar behavioral and cognitive anomalies characterized by increased fear and anxiety and decreased learning and memory abilities. Interestingly, both groups of animals presented increased plasma markers of endothelial/vascular dysfunction and permeability of cerebral vasculature and impaired mitochondrial enzymatic activities. In addition, a significant increase in Aβ levels was observed in the cortex and hippocampus of T2D mice. These results support the notion that T2D predisposes to cerebrovascular alterations, cognitive decline, and development of AD.

Page 637
Book Review: Are Alzheimer’s Disease and Aging Evolutionary? The Origin of Everything, by D.B. Kelley, 345 pp. Reviewed by George Perry, Roberto Rodrigues, Rudy J. Castellani