Volume 34, Number 2, February 2013

Pages 341-347
Review
Grazia Daniela Femminella*, Giuseppe Rengo*, Gennaro Pagano, Claudio de Lucia, Klara Komici, Valentina Parisi, Alessandro Cannavo, Daniela Liccardo, Carlo Vigorito, Pasquale Perrone Filardi, Nicola Ferrara, Dario Leosco *These authors contributed equally to this work
ß-Adrenergic Receptors and G Protein-Coupled Receptor Kinase-2 in Alzheimer’s Disease: A New Paradigm for Prognosis and Therapy?
Abstract: Alzheimer’s disease (AD) is a devastating form of dementia that imposes a severe burden on health systems and society. Although several aspects of AD pathogenesis have been elucidated over the last few decades, many questions still need to be addressed. In fact, currently available medications only provide symptomatic improvement in patients with AD without affecting disease progression. The ß-adrenergic receptor (ß-AR) system can be considered a possible target that deserves further exploration in AD. The central noradrenergic system undergoes substantial changes in the course of AD and ß-ARs have been implicated not only in amyloid formation in AD brain but also in amyloid-induced neurotoxicity. Moreover, clinical evidence suggests a protective role of ß-AR blockers on AD onset. In addition to that, post-receptor components of ß-AR signaling seem to have a role in AD pathogenesis. In particular, the G protein coupled receptor kinase 2, responsible for ß-AR desensitization and downregulation, mediates amyloid-induced ß-AR dysfunction in neurons, and its levels in circulating lymphocytes of AD patients are increased and inversely correlated with patient’s cognitive status. Therefore, there is an urgent need to gain further insight on the role of the adrenergic system components in AD pathogenesis in order to translate preclinical and clinical knowledge to more efficacious prognostic and therapeutic strategies.

Pages 349-365
Laurel O. Sillerud, Nathan O. Solberg, Ryan Chamberlain, Robert A. Orlando, John E. Heidrich, David C. Brown, Christina I. Brady, Thomas A. Vander Jagt, Michael Garwood, David L. Vander Jagt
SPION-Enhanced Magnetic Resonance Imaging of Alzheimer’s Disease Plaques in AβPP/PS-1 Transgenic Mouse Brain
Abstract: In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer’s disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-β plaques in AD. Here we report studies in AβPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AβPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-β detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice.

Supplementary Data for Sillerud et al. article (PDF)
Supplementary File for Sillerud et al. (.zip file containing a Mathematica .nb file)

Pages 367-375
Christoph Laske, Michael Schmohl, Thomas Leyhe, Elke Stransky, Walter Maetzler, Daniela Berg, Andreas J. Fallgatter, Thomas Joos, Janko Dietzsch
Immune Profiling in Blood Identifies sTNF-R1 Performing Comparably Well as Biomarker Panels for Classification of Alzheimer’s Disease Patients
Abstract: Background: Alzheimer’s disease (AD) has been linked to a state of cerebral and systemic inflammation. The objective of the present study was to determine whether singular markers or a set of inflammatory biomarkers in peripheral blood allow discrimination between AD patients and healthy controls at the individual level. Methods: Using bead based multiplexed sandwich immunoassays, 25 inflammatory biomarkers were measured in 164 serum samples from individuals with early AD and age-matched cognitively healthy elderly controls. The data set was randomly split into a training set for feature selection and classification training and a test set for class prediction of blinded samples (1:1 ratio) to evaluate the chosen predictors and parameters. Multivariate data analysis was performed with use of a support vector machine (SVM). Results: After selection of sTNF-R1 as most discriminative parameter in the training set, the application of SVM to the independent test dataset resulted in a 90.0% correct classification for individual AD and control subjects. Conclusions: We identified sTNF-R1 from a marker set consisting of 25 inflammatory biomarkers, which allowed SVM-based discrimination of AD patients from healthy controls on a single-subject classification level with a clinically relevant accuracy and validity. Although larger sample populations will be needed to confirm this diagnostic accuracy, our study suggests that sTNF-R1 in serum—either as singular marker or incorporated into a biomarker panel—could be a powerful new biomarker for detection of AD. In addition, selective inhibition of TNF-R1 function may represent a new therapeutic approach in AD.

Pages 377-385
Annachiara Cagnin, Alberta Leon, Daniela Vianello, Davide Colavito, Silvia Favaretto, Giulia Zarantonello, Anna Stecca, Mario Ermani, Alberto Zambon (Handling Associate Editor: Daniela Galimberti)
LDL Density and Oxidation are Modulated by PON1 Promoter Genotype in Patients with Alzheimer’s Disease
Abstract: Cholesterol metabolism alteration is a hot topic in the field of Alzheimer’s disease (AD). However, data on plasma lipoproteins cholesterol distribution and oxidation in AD and their possible genetic determinants are lacking. The paraoxonase-1 (PON1) gene -107C/T promoter polymorphisms have been found associated with AD. One of the fundamental functions of PON1 enzyme is the inhibition of low-density lipoproteins (LDL) oxidation. We therefore evaluated plasma lipoprotein profile and LDL density and oxidation in late-onset AD patients and healthy elderly subjects, without neuroimaging evidence of cerebrovascular lesions and not on lipid-lowering treatment, and their interaction with PON1 -107C/T and apolipoprotein E (APOE) genotypes. Mean plasma total cholesterol and LDL levels were higher in AD than controls (p<0.05). Lipoproteins cholesterol distribution shifted toward a greater prevalence of smaller, denser LDL (sd-LDL, p<0.05) only in AD patients with PON1 -107TT genotype, who also showed increased plasma levels of oxidized LDL (ox-LDL, p=0.02). A significant association was observed between sd-LDL and ox-LDL levels (p<005) in AD patients. APOE genotype did not modulate lipoprotein distribution. Increased levels of sd-LDL and ox-LDL particles in the AD PON1 TT patients could be explained by the combined effect of an AD-related pro-oxidant milieu and an ineffective PON1 gene polymorphism-related antioxidant capacity. The functional correlate of the association between PON1 -107C/T polymorphism and AD may be the abnormal modulation of LDL oxidation. Ox-LDL may amplify the processes of endothelial injury promoted by vascular amyloid deposition, which represents one of the potential pathways explaining the cross-road between vascular and neurodegenerative pathomechanisms in AD.

Supplementary Data for Cagnin et al. article (PDF)

Pages 387-397
Jana-Katharina Dieks, Joanna Gawinecka, Abdul R. Asif, Daniela Varges, Karin Gmitterova, Jan-Hendrik Streich, Hassan Dihazi, Uta Heinemann, Inga Zerr
Low-Abundant Cerebrospinal Fluid Proteome Alterations in Dementia with Lewy Bodies
Abstract: Dementia with Lewy bodies (DLB) is one of the most common neurodegenerative diseases and shares multiple clinical and neuropathological parallels with Alzheimer’s (AD) and Parkinson’s disease (PD). A variety of clinical signs are suggestive for the diagnosis, and imaging (βCIT SPECT) contributes substantially to the diagnosis. The study reported here was performed in search for a biomarker in the cerebrospinal fluid (CSF) of these patients. We applied 2D fluorescence difference gel electrophoresis and mass spectrometry to analyze the CSF proteome pattern of DLB patients after depleting twelve high-abundant proteins. The densitometric analysis of 2D gels showed the up- or down-regulation of 44 protein spots. Subsequently, 23 different proteins were identified. The majority is involved in acute phase and immune response. Many of these proteins were previously reported before as being associated with AD or PD, which strongly suggests a molecular cross-talk and may explain clinical and pathological overlap of these disease entities. Among the identified proteins are two highly upregulated proteins—inter alpha trypsin inhibitor heavy chain (ITIH4) and calsyntenin 1—that may have the potential to serve as molecular biomarkers specific for DLB. The identification of DLB-associated proteome changes will help to further understand pathological processes occurring in DLB and may provide future prospects to diagnostic and therapeutic options.

Supplementary Data for Dieks et al. article (PDF)

Pages 399-405
Mei Sian Chong*, Liang Kee Goh*, Wee Shiong Lim, Mark Chan, Laura Tay, Gengbo Chen, Lei Feng, Tze Pin Ng, Chay Hoon Tan, Tih Shih Lee (Handling Associate Editor: Barbara Borroni) *These authors contributed equally.
Gene Expression Profiling of Peripheral Blood Leukocytes Shows Consistent Longitudinal Downregulation of TOMM40 and Upregulation of KIR2DL5A, PLOD1, and SLC2A8 among Fast Progressors in Early Alzheimer’s Disease
Abstract: We previously reported TOMM40 was significantly down-regulated in whole blood of Alzheimer’s disease (AD) subjects. In this study, we examined whole blood gene profiling differences over a one-year period comparing early AD subjects based on disease progression. 6-monthly assessments and blood sampling on 29 probable AD subjects compared with age- and gender-matched controls were performed. AD subjects with change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score of ≥2 points/year were classified as fast-progressors and those with CDR-SB change of <2 points/year were classified as slow-progressors. We found statistically significant upregulation in KIR2DL5A, SLC2A8, and PLOD1 for fast- (n=8) compared with slow-progressors (n=21) across the time-points. TOMM40 gene expression remained significantly lower in AD patients at all time-points compared to controls, supporting our previous findings. Our novel findings of specific gene expression differences between fast- and slow-progressors in combination with consistently lower TOMM40 expression, suggest their potential role as prognostic blood biomarkers to predict progression in early AD.

Pages 407-415
Maria Chatzistavraki, Elli Kyratzi, Angeliki Fotinopoulou, Panagiota Papazafiri, Spiros Efthimiopoulos (Handling Associate Editor: Kumar Sambamurti)
Downregulation of AβPP Enhances Both Calcium Content of Endoplasmic Reticulum and Acidic Stores and the Dynamics of Store Operated Calcium Channel Activity
Abstract: The amyloid-β protein precursor (AβPP) is a type-1 transmembrane protein involved in Alzheimer’s disease (AD). It has become increasingly evident that AβPP, its protein-protein interactions, and its proteolytical fragments may affect calcium homeostasis and vice versa. In addition, there is evidence that calcium dysregulation contributes to AD. To study the role of AβPP in calcium homeostasis, we downregulated its expression in SH-SY5Y cells using shRNA (SH-SY5Y/AβPP-) or increased expression of AβPP695 by transfection (SH-SY5Y/AβPP+). The levels of cytosolic Ca2+ after treatment with thapsigargin, monensin, activation of capacitative calcium entry (CCE), and treatment with SKF, a store operated channel (SOCs) inhibitor, were measured by fura-2AM fluorimetry. SH-SY5Y/AβPP+ cells show reduced response to thapsigargin and reduced CCE, although this reduction is not statistically significant. On the other hand, we found that, relative to SH-SY5Y, SH-SY5Y/AβPP- cells show a significant increase in the response to thapsigargin but not in CCE and their SOCs were more susceptible to SKF inhibition. Additionally, downregulation of AβPP resulted in increased response to monensin that induces calcium release from acidic stores. The increase of calcium release from the endoplasmic reticulum and the acidic stores, when AβPP is downregulated, could be attributed to elevated Ca2+ content or to a dysregulation of Ca2+ transfer through their membranes. These data, along with already existing evidence regarding the role of AβPP in calcium homeostasis and the early occurring structural and functional abnormalities of endosomes, further substantiate the role of AβPP in calcium homeostasis and in AD.

Pages 417-429
Wei Zhao*, Lap Ho*, Merina Varghese, Shrishailam Yemul, Kristen Dams-O’Connor, Wayne Gordon, Lindsay Knable, Daniel Freire, Vahram Haroutunian, Giulio Maria Pasinetti *These authors contributed equally to this study.
Decreased Level of Olfactory Receptors in Blood Cells Following Traumatic Brain Injury and Potential Association with Tauopathy
Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability among children and young adults in the United States. In this study, we explored whether changes in the gene expression profile of peripheral blood mononuclear cells (PBMC) may provide a clinically assessable “window” into the brain, reflecting molecular alterations following TBI that might contribute to the onset and progression of TBI clinical complications. We identified three olfactory receptor (OR) TBI biomarkers that are aberrantly down-regulated in PBMC specimens from TBI subjects. Down-regulation of these OR biomarkers in PBMC was correlated with the severity of brain injury and TBI-specific symptoms. A two- biomarker panel comprised of OR11H1 and OR4M1 provided the best criterion for segregating the TBI and control cases with 90% accuracy, 83.3% sensitivity, and 100% specificity. We found that the OR biomarkers are ectopically expressed in multiple brain regions, including the entorhinal-hippocampus system known to play an important role in memory formation and consolidation. Activation of OR4M1 led to attenuation of abnormal tau phosphorylation, possibly through JNK signaling pathway. Our results suggested that addition of the two-OR biomarker model to current diagnostic criteria may lead to improved TBI detection for clinical trials, and decreased expression of OR TBI biomarkers might be associated with TBI-induced tauopathy. Future studies exploring the physiological relevance of OR TBI biomarkers in the normal brain and in the brain following TBI will provide a better understanding of the biological mechanisms underlying TBI and insights into novel therapeutic targets for TBI.

Supplementary Data for Zhao et al. article (PDF)

Pages 431-437
Josephine Barnes, Jonathan W. Bartlett, Nick C. Fox, Jonathan M. Schott, for the Alzheimer’s Disease Neuroimaging Initiative
Targeted Recruitment using Cerebrospinal Fluid Biomarkers: Implications for Alzheimer’s Disease Therapeutic Trials
Abstract: There is interest in using cerebrospinal fluid (CSF) biomarkers to enrich mild cognitive impairment (MCI) clinical trials; however, there are conflicting views on their utility. We identified MCI subjects with CSF from the Alzheimer’s Disease Neuroimaging Initiative. We measured brain and hippocampal atrophy rates, ventricular expansion rates, and decline in ADAS-Cog 13 and MMSE over one year. We examined proportionate and absolute reductions in mean outcome measures. Using a CSF Aβ1-42 cut-off (192 pg/ml), we estimated sample size ratios for clinical trials based on these outcomes for targeted (i.e., low-Aβ-MCI subjects only) compared with unrestricted recruitment. We further examined sample size ratios assuming only low-Aβ-MCIs would benefit from treatment. We found that for proportionate reductions in mean outcomes targeted recruitment led to significantly smaller sample sizes for all outcomes apart from ADAS-Cog. No sample size reduction was demonstrated for outcomes based on absolute reductions. Excluding subjects who would not benefit from treatment always reduces sample sizes. Using CSF biomarkers as inclusion criteria for AD trials increases the number of subjects needing to be screened but may reduce required sample sizes and reduce the risk of exposing patients without amyloid pathology to treatment side-effects. Whether targeted recruitment reduces required sample sizes depends critically on assumptions regarding treatment effects.

Supplementary Data for Barnes et al. article (PDF)

Pages 439-447
Elisa Porcellini, Ilaria Carbone, Pier Luigi Martelli, Manuela Ianni, Rita Casadio, Annalisa Pession, Federico Licastro (Handling Associate Editor: Calogero Caruso)
Haplotype of Single Nucleotide Polymorphisms in Exon 6 of the MZF-1 Gene and Alzheimer’s Disease
Abstract: Our previous works showed that single nucleotide polymorphisms (SNPs) in genes with regulatory function upon inflammatory response and cholesterol metabolism were associated with Alzheimer’s disease (AD) risk. The list comprises SNPs located on the promoters of alpha 1 antichymotrypsin (rs1884082), hydroxy methyl glutaryl coenzime A reductase (rs376140), tumor necrosis factor alpha (rs1800629), and interleukin 10 (rs1800869). Here we investigated the effect of these SNPs on the binding for transcription factors. We computationally detected putative binding sites for transcription factors located in the SNP regions. To this aim, the TESS program for scanning the promoter sequences against the binding-site models available at TRANSFACT and JASPAR databases was adopted. All the analyzed SNPs appeared to affect the binding of myeloid zinc finger 1 (MZF-1) to the promoter sequence of the above reported genes. Therefore 16 SNPs in MZF-1 gene were tested in 120 AD cases and 88 controls to asses a possible association between MZF-1 and AD. 14 SNPs showed no variability in AD and control populations, while two SNPs rs4756 and rs2228162 showed the three genotypes. Genotype distributions and allele frequencies of these two SNPs were comparable between AD and controls. On the other hand, the haplotype distribution of rs4756 and rs2228162 was different between AD and controls; being the AG haplotype associated with a decreased AD risk. In conclusion, selected SNPs in MZF-1 gene exert a minor effect on AD risk.

Supplementary Data for Porcellini et al. article (PDF)

Pages 449-456
Valory Pavlik, Paul Massman, Robert Barber, Rachelle Doody, for the Texas Alzheimer’s Research and Care Consortium (TARCC)
Differences in the Association of Peripheral Insulin and Cognitive Function in Non-Diabetic Alzheimer’s Disease Cases and Normal Controls
Abstract: Insulin resistance increases the risk of cognitive impairment and dementia, but higher insulin levels may be cognitively protective after a diagnosis of Alzheimer’s disease (AD). The role of peripheral insulin as a predictor of cognitive decline both before and after an AD diagnosis needs further elucidation. We studied 197 AD cases and 198 normal controls enrolled in the Texas Alzheimer’s Research Consortium. Standardized protocols were used to collect age, gender, education, body mass index (BMI), serum insulin (not restricted to fasting), hemoglobin A1c (HbA1c), lipids, smoking and cardiovascular disease history, and neuropsychological tests including Mini-Mental State Examination, American National Adult Reading Test (AMNART) errors, Controlled Word Association Test (COWAT), Boston Naming Test, Wechsler Memory Scale-Revised (WMSR) Digit Span, Trails A and B, WMSR Logical Memory (LM) I and II, and Visual Reproduction (VR) I and II. We used linear regression to test the contribution of log-transformed serum insulin to each score, adjusting for age, gender, education, and BMI. In the AD cases, higher serum insulin was associated with worse performance on the COWAT (p<0.001) and Trails B (p=0.04). In controls, higher serum insulin was associated with worse performance on the AMNART (p=0.005), COWAT (p=0.023), Digit Span (p=0.013), LM I (p=0.004), LM II (p=0.017), and marginally with VR II (p=0.058). Adjustment for HbA1c, APOE4, and cardiovascular disease, or restricting the sample to mild AD, did not alter these associations. In non-demented older individuals, higher peripheral insulin appears to be associated with worse cognitive performance in multiple domains, but is not a consistent predictor in AD cases. These findings indicate the need for additional research on the role of insulin in the transition between normal and impaired cognitive function.

Pages 457-468
David T. Chien, Shadfar Bahri, A. Katrin Szardenings, Joseph C. Walsh, Fanrong Mu, Min-Ying Su, William R. Shankle, Arkadij Elizarov, Hartmuth Kolb
Early Clinical PET Imaging Results with the Novel PHF-Tau Radioligand [F-18]-T807
Abstract: Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer’s disease. We have developed a novel PHF-tau targeting positron emission tomography imaging agent, [F-18]-T807, which may be useful for imaging Alzheimer’s disease and other tauopathies. Here, we describe the first human brain images with [F-18]-T807.

Supplementary Data for Chien et al. article (PDF)

Pages 469-483
Laurent Désiré, Elodie Blondiaux, Jennifer Carrière, Raphael Haddad, Olivier Sol, Pascale Fehlbaum-Beurdeley, Rich Einstein, Weiyin Zhou, Matthew P. Pando (Handling Associate Editor: Barbara Borroni)
Blood Transcriptomic Biomarkers of Alzheimer’s Disease Patients Treated with EHT 0202
Abstract: Monitoring the genomic expression of patients in clinical trials for Alzheimer’s disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease.

Supplementary Data for Désiré et al. article (PDF)
Supplementary Table 2 for Désiré et al. (.xls file)
Supplementary Table 3 for Désiré et al. (.xls file)

Pages 485-499
Isabelle Le Ber*, Agnès Camuzat*, Lena Guillot-Noel*, Didier Hannequin, Lucette Lacomblez, Véronique Golfier, Michèle Puel, Olivier Martinaud, Vincent Deramecourt, Sophie Rivaud-Pechoux, Stéphanie Millecamps, Martine Vercelletto, Philippe Couratier, François Sellal, Florence Pasquier, François Salachas, Catherine Thomas-Antérion, Mira Didic, Jérémie Pariente, Danielle Seilhean, Merle Ruberg, Isabelle Wargon, Frédéric Blanc, William Camu, Bernard-François Michel, Eric Berger, Mathilde Sauvée, Christel Thauvin-Robinet, Karl Mondon, Elisabeth Tournier-Lasserve, Cyril Goizet, Marie Fleury, Gabriel Viennet, Patrice Verpillat, Vincent Meininger, Charles Duyckaerts, Bruno Dubois, Alexis Brice, and the French research network on FTLD/FTLD-ALS *These authors contributed equally to this work.
C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flowchart for Genetic Testing
Abstract: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p=0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p=0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

Supplementary Data for Le Ber et al. article (PDF)

Pages 501-507
Yonas E. Geda, Marion Ragossnig, Lewis A. Roberts, Rosebud O. Roberts, V. Shane Pankratz, Teresa J.H. Christianson, Michelle M. Mielke, James A. Levine, Bradley F. Boeve, Ondřej Sochor, Eric G. Tangalos, David S. Knopman, Ronald C. Petersen
Caloric Intake, Aging, and Mild Cognitive Impairment: A Population-Based Study
Abstract: In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70–92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, gender, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53–1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26–3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship.

Pages 509-518
Janaína Espinosa, Andreia Rocha, Fernanda Nunes, Marcelo S. Costa, Vanessa Schein, Vanessa Kazlauckas, Eduardo Kalinine, Diogo O. Souza, Rodrigo A. Cunha, Lisiane O. Porciúncula (Handling Associate Editor: Alexandre de Mendonça)
Caffeine Consumption Prevents Memory Impairment, Neuronal Damage, and Adenosine A2a Receptors Upregulation in the Hippocampus of a Rat Model of Sporadic Dementia
Abstract: Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer’s disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.

Pages 519-528
Marie-Laure Ancelin, Emmanuelle Ripoche, Anne-Marie Dupuy, Pascale Barberger-Gateau, Sophie Auriacombe, Olivier Rouaud, Claudine Berr, Isabelle Carrière, Karen Ritchie
Sex Differences in the Associations between Lipid Levels and Incident Dementia
Abstract: Cholesterol is a risk factor for developing vascular pathologies, which is in turn an important risk factor for dementia. Previous studies linking lipids and dementia have yielded inconsistent results, which may be attributable to sex differences in the etiology of both vascular disease and dementia. The aim of this study was to evaluate the associations between lipids and incident dementia in 7053 community-dwelling elderly. Dementia was diagnosed at baseline, and 2, 4, and 7-year follow-up. Multivariate Cox models stratified by sex and history of vascular pathologies at baseline were adjusted for sociodemographic, mental and physical health variables, and genetic vulnerability. In men without vascular pathologies, an increased incidence of all-cause dementia but not Alzheimer’s disease (AD) was associated with high triglyceride (TG) (HR=1.55, 95%CI=1.04-2.32, p=0.03) and low HDL-cholesterol levels (HR=1.49, 95%CI=0.99-2.23, p=0.05). In women without vascular pathologies, low TG levels were associated with a decreased risk of AD (HR=0.65, 95%CI=0.43-0.97, p=0.03). A decreased risk was also found with high TG levels which may depend on genetic vulnerability to dyslipidemia related to APOA5. For both sexes, no significant associations were found between total- or LDL-cholesterol and dementia or AD. Low HDL-cholesterol and high TG levels may be risk factors of dementia in elderly men whereas low TG is associated with decreased incident AD in women. This data suggests a complex sex-specific etiology of vascular dementia and AD.

Pages 529-536
Brittany N. Dugger, Jose A. Hidalgo, Glenn Chiarolanza, Monica Mariner, Jonette Henry-Watson, Lucia I. Sue, Thomas G. Beach
The Distribution of Phosphorylated Tau in Spinal Cords of Alzheimer’s Disease and Non-Demented Individuals
Abstract: Abnormal phosphorylation of the microtubule-associated protein tau develops in selected brain regions in normal aging and becomes widespread throughout the brain in Alzheimer’s disease (AD). Braak and others have described the distribution of neurofibrillary tangles and deposition of abnormally phosphorylated tau (p-tau) and correlated this with the progressive cognitive dysfunction in AD. However, to date there have been no comprehensive studies examining abnormally phosphorylated tau deposition in the spinal cord as part of normal aging or AD. We investigated, using immunohistochemical methods, the presence of p-tau in the spinal cord of 46 cases with a clinicopathological diagnosis of AD as well as 37 non-demented (ND) individuals lacking any defined central nervous system-related clinicopathological diagnosis. We found the cervical cord segments to be the most frequently affected subdivision (96% AD versus 43% ND), followed by thoracic (69% AD versus 37% ND), lumbar (65% AD versus 27% ND), and sacral (53% AD versus 13% ND). The spinal cord was often affected at early-stage brain disease, with p-tau spinal cord immunoreactivity in 40% of subjects at Braak neurofibrillary stage I; however, there were no cases having spinal cord p-tau that did not have p-tau within the brain. As p-tau immunoreactivity is present within the spinal cords of ND as well as AD subjects, it is likely that the phosphorylation of spinal cord tau occurs in the preclinical stage of AD, prior to dementia. The presence of significant spinal cord p-tau-immunoreactive pathology has important implications for both the pathogenesis and clinical manifestations of AD.

Pages 537-546
Nicole S. Schmid, Kirsten I. Taylor, Nancy S. Foldi, Manfred Berres, Andreas U. Monsch (Handling Associate Editor: Mark Bondi)
Neuropsychological Signs of Alzheimer’s Disease 8 Years Prior to Diagnosis
Abstract: We investigated the earliest neuropsychological changes in Alzheimer’s disease (AD) by comparing the baseline performance of 29 individuals who subsequently developed AD within an average of 7.91 ± 2.70 years with 29 pairwise-matched individuals who remained cognitively healthy (NC). We hypothesized that subtle, qualitative changes in cognition precede clinical AD by several years, and therefore examined subjective as well as standard quantitative measures of cognition, in addition to subjective estimates of mood and medical status. Participants were selected from the 825 members of the longitudinal BASEL study (BAsel Study on the ELderly), all of whom had been ApoE-genotyped and received comprehensive bi-annual neuropsychological assessments. Within 13 years, 29 were diagnosed with probable AD. Each individual who progressed to AD (AD-P) was pairwise matched to a NC participant based on age, education, demographic status, observation period, and, importantly, ApoE genotype. A regression analysis using the lasso technique identified which of 115 neuropsychological variables best discriminated baseline NC from baseline AD-P performance. This analysis yielded eleven neuropsychological variables that optimally discriminated the two groups (correct classification rate: 60.4%): 1) Intrusions and 2) response bias in verbal learning and memory tasks; 3) delayed figure recall; 4.-6) three Wechsler Adult Intelligence Scale (WAIS) Block Design subtest variables; 7.-8) number of errors and repetitions on letter fluency; and 9.-11) self-report of memory problems, a feeling of sadness, and cardiac problems. These results suggest that the preclinical neuropsychological cascade to AD includes subtle but identifiable qualitative impairments in verbal and visual memory, visuospatial processing, error control, and subjective neuropsychological complaints.

Supplementary Data for Schmid et al. article (PDF)

Pages 547-559
Donald R. Royall, Raymond F. Palmer, Eric D. Vidoni, Robyn A. Honea
The Default Mode Network may be the Key Substrate of Depressive Symptom-Related Cognitive Changes
Abstract: Depressive symptoms are associated with an increased risk of Alzheimer’s disease (AD) but the mechanism(s) involved has not been well established. In a convenience sample of participants in the University of Kansas’ Brain Aging Project, we use structural equation modeling (SEM) to explicitly distinguish depressive symptom-related variance in cognitive task performance (i.e., DEPCOG) from that which is unrelated to a depressive symptoms. DEPCOG is strongly associated with the cognitive correlates of functional status (δ), which we previously associated with elements of the Default Mode Network (DMN). Both δ and DEPCOG map to a posterior cingulate seeded network that has recently been associated with amyloid-β deposition and includes elements of the DMN. Both contribute significantly to clinical dementia status and dementia severity, as measured by the Clinical Dementia Rating Scale Sum of Boxes. These findings suggest that the cognitive correlates of depressive symptoms, even in the absence of a major depressive episode, may contribute to dementia in their own right, and could be responsible for some cases of incident clinical “AD”. This conclusion suggests new opportunities for the latter’s diagnosis, prevention, and treatment.

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