Volume 29, Number 4, April 2012

Pages 711-726
Fiona E. Harrison (Handling Associate Editor: Cristina Polidori)
A Critical Review of Vitamin C for the Prevention of Age-Related Cognitive Decline and Alzheimer’s Disease
Abstract: Antioxidants in the diet have long been thought to confer some level of protection against the oxidative damage that is involved in the pathology of Alzheimer’s disease as well as general cognitive decline in normal aging. Nevertheless, support for this hypothesis in the literature is equivocal. In the case of vitamin C (ascorbic acid) in particular, lack of consideration of some of the specific features of vitamin C metabolism has led to studies in which classification of participants according to vitamin C status is inaccurate, and the absence of critical information precludes the drawing of appropriate conclusions. Vitamin C levels in plasma are not always reported, and estimated daily intake from food diaries may not be accurate or reflect actual plasma values. The ability to transport ingested vitamin C from the intestines into blood is limited by the saturable sodium-dependent vitamin C transporter (SVCT1) and thus very high intakes and the use of supplements are often erroneously considered to be of greater benefit that they really are. The current review documents differences among the studies in terms of vitamin C status of participants. Overall, there is a large body of evidence that maintaining healthy vitamin C levels can have a protective function against age-related cognitive decline and Alzheimer’s disease, but avoiding vitamin C deficiency is likely to be more beneficial than taking supplements on top of a normal, healthy diet.

Pages 727-740
Zan-Chao Liu*, Zheng-Qi Fu*, Jie Song, Jia-Yu Zhang, Yu-Ping Wei, Jiang Chu, Li Han, Na Qu, Jian-Zhi Wang, Qing Tian (Handling Associate Editor: Xiongwei Zhu) *These authors contributed equally to this manuscript.
Bip Enhanced the Association of GSK-3β with Tau During ER StressBoth in vivo and in vitro
Abstract: Hyperphosphorylated tau is the major component of intracellular neurofibrillary tangles, which is positively correlated with the cognitive decline in Alzheimer’s disease (AD). The upstream factors leading to tau hyperphosphorylation are still not fully understood. Endoplasmic reticulum (ER) stress has been indicated in AD pathogenesis and the increased level of binding immunoglobulin protein (Bip), an important ER associated chaperon, is increased in AD brain. Here hyperphosphorylation of tau, activation of glycogen synthase kinase-3β (GSK-3β), and elevation of Bip were induced by ventricular infusion of ER stressors, tunicamycin (TM) and thapsigargin (TG), in rats. GSK-3β was found to be responsible for tau hyperphosphorylation induced by ER stressors both in vivo and in vitro. In addition, inhibited Akt, protein tyrosine phosphatase 1B, and activated Fyn were detected in vivo. Down-regulating Bip by tranfecting its siRNA plasmid significantly revised tau hyperphosphorylation in TG treated HEK293/tau cells, but the activation of GSK-3β was still observed. By immunoprecipitation, we found that the binding levels of Bip to tau and GSK-3β were significantly increased with the elevation of Bip in TM-treated rats. Moreover, in Bip overexpressed HEK293/tau cells, the binding levels of Bip to tau (mainly phosphorylated tau) and GSK-3β were also significantly increased. However, β-catenin, another important substrate of GSK-3β, was not found bound to the increased Bip. All these data suggest an essential role of Bip in GSK-3β dependent tau hyperphosphorylation in ER stress by promoting the binding of GSK-3β to tau.

Pages 741-749
Julia Miralbell, Gabriela Spulber, Babak Hooshmand, Ariadna Besga, Maria Mataró, Angel Cedazo-Minguez, Miia Kivipelto, Lars-Olof Wahlund
Grey Matter and Cognitive Patterns in Cognitive Impaired Subjects Using CSF Biomarker Cut-Offs
Abstract: The aim of this study was to investigate brain tissue volumes, grey matter (GM) distribution, and cognitive performance for cognitively impaired subjects using cerebrospinal fluid (CSF) biomarker cut-offs as grouping criteria. 41 subjects attending the Memory Clinic, Karolinska University Hospital, Huddinge, Sweden, were divided into groups based on normal or abnormal CSF levels of Aβ1-42, t-tau, and p-tau181. SIENAX algorithms were employed for brain tissue volumes estimation and voxel-based morphometry (VBM) for mapping the differences in GM patterns. VBM revealed significant lower GM volumes in temporo-parietal, occipital, and prefrontal cortices for those subjects belonging to abnormal CSF t-tau and p-tau181 groups. No differences were found between groups according to CSF Aβ1-42 cut-offs. Patients with abnormal CSF p-tau181 showed lower cognitive performance compared to those with normal levels. Patients with abnormal levels of CSF tau (but not Aβ1-42) showed an Alzheimer’s disease-like pattern for both GM distribution and cognitive profile, compared to those with normal levels. These results support the hypothesis that CSF t-tau or p-tau181 levels may be of direct value for the evaluation of disease severity.

Supplementary Data for Miralbell et al. article (PDF)

Pages 751-759
Danilo Di Bona, Claudia Rizzo, Giuseppe Bonaventura, Giuseppina Candore, Calogero Caruso (Handling Associate Editor: Robert Monastero)
Association Between Interleukin-10 Polymorphisms and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: It has been hypothesized that polymorphisms of interleukin (IL)-10 genes affect the risk of developing late onset Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the IL-10 gene with AD risk. Fifteen studies investigating the association between IL-10 polymorphisms (-1082, -819, -592) and AD were found and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested an association between -1082 polymorphism and AD risk with a marginal statistical significance (GG versus AG/AA: pooled odds ratio [OR]: 0.82, 95% confidence interval CI: 0.65–1.02) and evidence of a moderate degree of between-study heterogeneity (χ2=27.13, d.f.=13, p=0.01, I2=52%). For the -819 and -592 polymorphisms, we did not find an association with AD, but significant between-study heterogeneity made genotype data pooling unacceptable. Analysis by IL-10 haplotype showed that the -1082G/-819C/-592C haplotype is associated with a lower risk of AD, although with a marginal statistical significance, probably due to the low number of studies included (GCC versus other genotypes: OR: 0.61, 95% CI: 0.32–1.15; I2: 85%). Current findings suggest a possible association between -1082 A>G polymorphism and the risk of developing AD; this effect is more evident in the oldest patients. The high degree of between-study heterogeneity, due to several underpowered studies and to other methodological problems of individual studies underlies the need for further methodologically adequate studies.

Pages 761-772
Gianfranco Spalletta, Paolo Girardi, Carlo Caltagirone, Maria Donata Orfei
Anosognosia and Neuropsychiatric Symptoms and Disorders in Mild Alzheimer Disease and Mild Cognitive Impairment
Abstract: Anosognosia is a multidimensional phenomenon that negatively affects course of illness. This study aimed to explore the association between anosognosia and neuropsychiatric phenomena in mild Alzheimer’s disease (AD) and in mild cognitive impairment (MCI). The Anosognosia Questionnaire for Dementia to assess anosognosia, and the Neuropsychiatric Inventory to assess neuropsychiatric symptoms were administered to 209 patients (103 mild AD, 52 amnestic-MCI, and 54 amnestic multidomain-MCI). Categorical diagnoses of apathy, depression, and psychosis were made using specific criteria for dementia. With regard to continuous scores, in mild AD, we found positive correlation between symptoms of anosognosia and apathy, agitation and aberrant motor behaviors, while in MCI, we did not find significant association. At a categorical level, the diagnosis of anosognosia in mild AD was associated with the diagnosis of apathy. In mild AD, the frequent co-occurrence of frontally mediated behavioral disorders and anosognosia, particularly apathy, supports the hypothesis of a shared neuropsychogenic process due to the disruption of frontal brain networks.

Pages 773-782
Cinta Valls-Pedret, Rosa Maria Lamuela-Raventós, Alexander Medina-Remón, Melibea Quintana, Dolores Corella, Xavier Pintó, Miguel Ángel Martínez-González, Ramon Estruch, Emilio Ros (Handling Associate Editor: Vincenza Frisardi)
Polyphenol-Rich Foods in the Mediterranean Diet are associated with Better Cognitive Function in Elderly Subjects at High Cardiovascular Risk
Abstract: Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n=447; 52% women; age 55-80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function. We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151-1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010-0.316) and 0.294 (0.055-0.534), respectively]; walnuts with working memory [1.191 (0.061-2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006-0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236-2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Pages 783-791
Li-Min Chua, Mei-Li Lim, Pey-Rou Chong, Ze Ping Hu, Nam Sang Cheung, Boon-Seng Wong (Handling Associate Editor: Xiongwei Zhu)
Impaired Neuronal Insulin Signaling Precedes Aβ42 Accumulation in Female AβPPsw/PS1DE9 Mice
Abstract: Reduced glucose utilization is likely to precede the onset of cognitive deficits in Alzheimer’s disease (AD). Similar aberrant glucose metabolism can also be detected in the brain of several AD mouse models. Although the cause of this metabolic defect is not well understood, it could be related to impaired insulin signaling that is increasingly being reported in AD brain. However, the temporal relationship between insulin impairment and amyloid-β (Aβ) biogenesis is unclear. In this study using female AβPPsw/PS1DE9 mice, we found that the level of Aβ40 was fairly constant in 6- to 15-month-old brains, whereas Aβ42 was only significantly increased in the 15-month-old brain. In contrast, increased levels of IRβ, IGF-1R, IRS1, and IRS-2, along with reduced glucose and insulin content, were detected earlier in the 12-month-old brains of AβPPsw/PS1DE9 mice. The reduction in brain glucose content was accompanied by increased GLUT3 and GLUT4 levels. Importantly, these changes precede the significant upregulation of Aβ42 level in the 15-month-old brain. Interestingly, reduction in the p85 subunit of PI3K was only apparent in the 15-month-old AβPPsw/PS1DE9 mouse brain. Furthermore, the expression profile of IRβ, IRS-2, and p85/PI3K in AβPPsw/PS1DE9 was distinct in wild-type mice of a similar age. Although the exact mechanisms underlining this connection remain unclear, our results suggest a possible early role for insulin signaling impairment leading to amyloid accumulation in AβPPsw/PS1DE9 mice.

Pages 793-808
Kyung Hwa Kim, Minho Moon, Saet-Byeol Yu, Inhee Mook-Jung, Jong-Il Kim
RNA-Seq Analysis of Frontal Cortex and Cerebellum from 5XFAD mice at Early Stage of Disease Pathology
Abstract: The pathogenesis of Alzheimer’s disease (AD), especially the early events of AD pathology, remains unknown because of the complexity of AD and limitation of analysis methods. Transcriptome analysis has provided comprehensive insights to investigate the complex cellular activity in brain, but the transcriptome profiles from AD patients with microarray have generated discordant results. Here, for the first time, we performed transcriptome analysis of frontal cortex and cerebellum in 7-week-old 5XFAD transgenic mice (before extracellular amyloid plaque deposits) using high-throughput RNA-Seq analysis. Specific functional annotations were identified with differentially expressed genes (DEGs) of frontal cortex (a typically vulnerable region of AD pathology) and cerebellum (a typically non-vulnerable region of AD pathology). Cardiovascular disease-related genes were significantly found in down-regulated DEGs of frontal cortex, and mitochondrial dysfunction-related genes were evident in down-regulated DEGs of cerebellum. Additionally, we found RNA variants at the nucleotide level in transgenic mice compared with non-transgenic mice. Our results indicate that both frontal cortex and cerebellum in 5XFAD transgenic mice show specific pathological processes in the early pathophysiology of AD.

Supplementary Data for Kim et al. article (PDF)

Pages 809-816
Mirko Bibl, Marion Gallus, Volker Welge, Hermann Esselmann, Jens Wiltfang (Handling Associate Editor: Brit Mollenhauer)
Aminoterminally Truncated and Oxidized Amyloid-β Peptides in the Cerebrospinal Fluid of Alzheimer’s Disease Patients
Abstract: Carboxyterminally elongated and aminoterminally truncated amyloid-β (Aβ) peptides and their oxidized derivates are major constituents of human amyloid plaques. The objective of the present study was to clarify the diagnostic impact of the Aβ peptides 1-38ox, 2-40, and 2-42 peptides on the neurochemical cerebrospinal fluid (CSF) diagnosis of Alzheimer’s disease (AD). For this purpose, 22 patients with AD and 20 non-demented disease controls (NDC) were comparatively analyzed for their cerebrospinal fluid pattern of Aβ1-38ox, Aβ2-40, and Aβ2-42 along with Aβ1-37, Aβ1-38, Aβ1-39, Aβ1-40, Aβ1-40ox, and Aβ1-42 using a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol and subsequent analysis in the Aβ-SDS-PAGE/immunoblot. The Aβ peptides 1-38ox, 2-40, and 2-42 could not be consistently detected in the investigated CSF samples, which applied to samples from AD and NDC patients alike. Otherwise, our approach revealed a striking decrease of Aβ1-42 and Aβ2-42, but not of Aβ1-38ox and Aβ2-40 in AD. Both Aβ1-42 and Aβ2-42 reached reasonable accuracies for diagnosing AD alone as well as in relation to Aβ1-40, Aβ1-38, or the sum of all measured Aβ peptides. Aβ1-38ox was negatively correlated to the Mini-Mental Status Examination score of AD patients, indicating that this peptide to linked to disease severity. We conclude that an exact analysis of CSF Aβ peptides regarding their carboxy- and aminoterminus as well as posttranslational modification may be a promising approach for diagnosing and tracking AD.

Pages 817-826
Margaux Perrin, Marie-Anne Henaff, Catherine Padovan, Isabelle Faillenot, Adrien Merville, Pierre Krolak-Salmon
Influence of Emotional Content and Context on Memory in Mild Alzheimer’s Disease
Abstract: Healthy subjects remember emotional stimuli better than neutral, as well as stimuli embedded in an emotional context. This better memory of emotional messages is linked to an amygdalo-hippocampal cooperation taking place in a larger fronto-temporal network particularly sensitive to pathological aging. Amygdala is mainly involved in gist memory of emotional messages. Whether emotional content or context enhances memory in mild Alzheimer’s disease (AD) patients is still debated. The aim of the present study is to examine the influence of emotional content and emotional context on the memory in mild AD, and whether this influence is linked to amygdala volume. Fifteen patients affected by mild AD and 15 age-matched controls were submitted to series of negative, positive, and neutral pictures. Each series was embedded in an emotional or neutral sound context. At the end of each series, participants had to freely recall pictures, and answer questions about each picture. Amygdala volumes were measured on patient 3D-MRI scans. In the present study, emotional content significantly favored memory of gist but not of details in healthy elderly and in AD patients. Patients’ amygdala volume was positively correlated to emotional content memory effect, implying a reduced memory benefit from emotional content when amygdala was atrophied. A positive context enhanced memory of pictures in healthy elderly, but not in AD, corroborating early fronto-temporal dysfunction and early working memory limitation in this disease.

Pages 827-840
Mark S. Kindy, Jin Yu, Hong Zhu, Salim S. El-Amouri, Vivian Hook, Gregory R. Hook
Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer’s Disease Mouse Model Expressing AβPP Containing the Wild-Type β-Secretase Site Sequence
Abstract: Therapeutic agents that improve the memory loss of Alzheimer’s disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London g-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients.

Supplementary Data for Kindy et al. article (PDF)

Pages 941-852

Gonzalo León, Javier DeFelipe, Alberto Muñoz
Effects of Amyloid-β Plaque Proximity on the Axon Initial Segment of Pyramidal Cells
Abstract: The output of cortical pyramidal cells reflects the balance between excitatory inputs of cortical and subcortical origin, and inhibitory inputs from distinct populations of cortical GABAergic interneurons, each of which selectively innervate different domains of neuronal pyramidal cells (i.e., dendrites, soma and axon initial segment [AIS]). In Alzheimer’s disease (AD), the presence of amyloid-β (Aβ) plaques alters the synaptic input to pyramidal cells in a number of ways. However, the effects of Aβ plaques on the AIS have still not been investigated to date. This neuronal domain is involved in input integration, as well as action potential initiation and propagation, and it exhibits Ca2+- and activity-dependent structural plasticity. The AIS is innervated by GABAergic axon terminals from chandelier cells, which are thought to exert a strong influence on pyramidal cell output. In the AβPP/PS1 transgenic mouse model of AD, we have investigated the effects of Aβ plaques on the morphological and neurochemical features of the AIS, including the cisternal organelle, using immunocytochemistry and confocal microscopy, as well as studying the innervation of the AIS by chandelier cell axon terminals. There is a strong reduction in GABAergic terminals that appose AIS membrane surfaces that are in contact with Aβ plaques, indicating altered inhibitory synapsis at the AIS. Thus, despite a lack of gross structural alterations in the AIS, this decrease in GABAergic innervation may deregulate AIS activity and contribute to the hyperactivity of neurons in contact with Aβ plaques.

Pages 853-861
Jennifer C. Palmer, Rachel Barker, Patrick G. Kehoe, Seth Love (Handling Associate Editor: Jack de la Torre)
Endothelin-1 is Elevated in Alzheimer’s Disease and Upregulated by Amyloid-β
Abstract: Vascular dysfunction and lowered cerebral blood flow are thought to contribute to the development and progression of Alzheimer’s disease (AD). Endothelin-1 (ET-1) is a potent vasoconstrictor, the production of which is mainly catalyzed by endothelin-converting enzymes (ECEs). We previously showed that ECE-2 is upregulated by amyloid-β (Aβ), and its expression elevated in AD postmortem brain tissue. We have now investigated whether there is a concomitant increase in ET-1. We studied temporal cortex from 20 cases of sporadic AD and 20 matched controls. The cellular distribution of ET-1 was assessed immunohistochemically in paraffin sections. PreproET-1 (EDN1) mRNA and ET-1 protein weres measured in homogenates of superior temporal cortex by real-time PCR and sandwich ELISA respectively. Cultured SH-SY5Y human neuroblastoma cells were incubated with 10 µM oligomeric Aβ42 for 24 h, and ET-1 protein level was measured in cell culture supernatants by sandwich ELISA. Antibody to ET-1 labeled neurons throughout the temporal cortex, and the walls of some cerebral blood vessels. ET-1 mRNA measured in the temporal neocortex was significantly elevated in AD when normalized for expression of GAPDH (p = 0.0256) or the neuronal marker neuron-specific enolase (NSE, p = 0.0001). ET-1 protein was also significantly higher in AD than in control tissue, when adjusted for neuronal content by measurement of NSE (p = 0.0275). ET-1 protein in SH-SY5Y cell supernatant rose 1.7-fold after exposure to 10 μM oligomeric Aβ (p = 0.024). These findings provide evidence of overactivity of the endothelin system in AD, further supporting the suggestion that endothelin receptor antagonists may be of value for the treatment of this disease.

Supplementary Data for Palmer et al. article (PDF)

Pages 863-873
Nancy Beyer, David T.R. Coulson, Shirley Heggarty, Rivka Ravid, Jan Hellemans, G. Brent Irvine, Janet A. Johnston (Handling Associate Editor: Ashley Bush)
Zinc Transporter mRNA Levels in Alzheimer’s Disease Postmortem Brain
Abstract: Zinc (Zn2+) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer’s disease (AD). Altered protein levels of the membrane Zn2+ transporters ZnT1, ZnT4, and ZnT6 have been reported in AD postmortem brain tissue. The present study analyzed mRNA levels of five established (LIV1, ZIP1, ZnT1, ZnT4, and ZnT6) and one potential (PRNP) Zn2+ transporter in human postmortem brain tissue from Braak-staged individuals with AD and controls using quantitative real-time PCR. Four cortical regions (middle temporal gyrus, superior occipital gyrus, superior parietal gyrus, and superior frontal gyrus) and cerebellum were examined. PRNP mRNA levels were decreased by ~30% in all four cortical regions examined in AD patients, but unchanged in the cerebellum. In contrast, some increases in mRNA levels of the other more established Zn2+ transporters (LIV1, ZIP1, ZnT1, ZnT6) were found in AD cortex. The ratios of the mRNA levels of LIV1, ZIP1, ZnT1, ZnT4, and ZnT6/mRNA level of neuron specific enolase increased significantly as the disease progressed and Braak stage increased. Significant correlations were also identified between mRNA levels of several of the Zn2+ transporters investigated. These expression changes could either reflect or cause the altered cortical Zn2+ distribution in AD, potentially increasing the likelihood of interactions between Zn2+ and Aβ or tau protein.

Pages 975-881
Matthew Mold, Annette K Shrive, Christopher Exley
Serum Amyloid P Component Accelerates the Formation and Enhances the Stability of Amyloid Fibrils in a Physiologically Significant Under-Saturated Solution of Amyoid-β42
Abstract: The mechanism whereby an under-saturated solution of amyloid-β (Aβ)42 precipitates as β sheets ins vivo in Alzheimer’s disease remains to be elucidated. Herein we present in vitro evidence that serum amyloid P component may mediate this process through its acceleration of amyloid formation from an under-saturated solution of Aβ42 and subsequently its stabilization of the amyloid fibrils formed over physiologically significant timeframes. Our observations support serum amyloid P component as a therapeutic target in Alzheimer’s disease.

Pages 883-890
Barbara Borroni, Mario Grassi, Enrico Premi, Antonella Alberici, Maura Cosseddu, Vanessa Cancelli, Federico Caobelli, Barbara Paghera, Alessandro Padovani (Handling Associate Editor: Davide Chiasserini)
Is Long-Term Prognosis of Frontotemporal Lobar Degeneration Predictable by Neuroimaging? Evidence from a Single-Subject Functional Brain Study
Abstract: Prediction of survival in frontotemporal lobar degeneration (FTLD) is guesswork. The aim of the present study was to evaluate whether SPECT scan may be useful to predict prognosis of long term survival in FTLD patients. A cohort of 125 patients with FTLD who underwent brain SPECT scan at the time of enrollment and who were further followed up for at least one year were considered. In each subject, volume of interests (VOIs) covering frontotemporal and parietal regions, bilaterally, were drawn. Principal component analysis (PCA) was applied on VOIs, and a Cox regression model was carried out to find out best predictors of survival. A two-pattern PCA solution was chosen, explaining more than 70% of variance, and “frontal” PC1 and “temporal” PC2 components were identified. The frontal PC1 was associated with higher rate of faster progression (HR=2.06, 95%CI=1.23-3.44, p=0.006 for univariate model, and HR=1.85, 95%CI=1.04-3.28, p=0.03 for multivariate model). In particular, right orbitofrontal cortex showed the higher loadings in PC1; the worse the scores of this region the shorter the survival was reported. We suggest that SPECT imaging, beyond a helpful tool in diagnostic assessment, may be an easily and accessible marker of disease outcome in FTLD. Further studies considering structural neuroimaging are warranted.

Supplementary Data for Borroni et al. article (PDF)

Pages 891-902
Franck Le Duff , Aude Emmanuelle Develay, Julien Quetel, Pierre Lafay, Stéphane Schück, Christian Pradier, Philippe Robert and the participating centers
The 2008–2012 French Alzheimer Plan: Description of the National Alzheimer Information System
Abstract: In France, one of the aims of the current national Alzheimer’s disease plan is to collect data from all memory centers (memory units, memory resource and research centers, independent neurologists) throughout the country. Here we describe the French Alzheimer Information System and present a ‘snapshot’ of the data collected throughout the country during the first year of operation. We analyzed all data transmitted by memory centers between January 2010 and December 2010. Each participating center is required to transmit information on patients to the French National Alzheimer dataBank (BNA). This involves completing a computer file containing 31 variables corresponding to a limited data set on AD (CIMA: Corpus minimum d’information Alzheimer). In 2010, the BNA received data from 320 memory centers relating to 199,113 consultations involving 118,776 patients. An analysis of the data shows that the initial MMSE (Mini Mental State Examination) mean score for patients in France was 16.8 points for Alzheimer’s disease, 25.7 points for mild cognitive impairment, and 18.8 points for ‘related disorders related disorders. The BNA will provide longitudinal data that can be used to assess the needs of individual local health areas and size specialized care provision in each regional health scheme. By contributing to the BNA, the memory centers enhance their clinical activity and help to advance knowledge in epidemiology and medical research in the important field of Alzheimer’s disease and related dementias.

Pages 903-911
Sarah Benisty, Sonia Reyes, Ophelia Godin, Dominique Hervé, Nikola Zieren, Eric Jouvent, Yicheng Zhu, Marco During, Martin Dichgans, Hugues Chabriat
White-Matter Lesions without Lacunar Infarcts in CADASIL
Abstract: To better characterize the clinical spectrum related to white-matter hyperintensities (WMH) in small vessel disease, 66 patients with WMH but without any lacunar infarct were selected out of a cohort of 248 CADASIL individuals. Characteristics of these patients were compared to those of patients with lacunar infarcts. Relationships between the normalized volume of WMH (nWMH), presence of microhemorrhages, brain parenchymal fraction (BPF). and cognitive performances were assessed by multiple linear regression. The Trail Making Test (TMT) A and B times, Mattis Dementia Rating Scale (MDRS) total score, attention subscore, verbal fluency score and delayed memory recall were significantly correlated with nWMH but not with BPF. Presence of microhemorrhages was associated with worse TMT B time and attention MDRS subscore after adjustment for WMH. All subjects had Mini-Mental Status Examination scores ≥24 and presented with no or only mild disability. These results suggest that CADASIL patients with isolated WMH can present with executive and attention deficit but not with severe disability and that additional lesions are needed to cause significant disability and/or dementia.

Pages 913-919
Serena Bucossi*, Renato Polimanti* Stefania Mariani, Mariacarla Ventriglia, Cristian Bonvicini, Simone Migliore, Dario Manfellotto, Carlo Salustri, Fabrizio Vernieri, Paolo M. Rossini, Rosanna Squitti (Handling Associate Editor: Roberta Ghidoni) *These authors contributed equally to the manuscript.
Association of K832R and R952K SNPs of Wilson’s Disease Gene with Alzheimer’s Disease
Abstract: Copper homeostasis appears abnormal in Alzheimer’s disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson’s disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12 - 2.60); p= 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19 - 2.80); p = 0.006] ATP7B SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D’ = 0.79) and controls (D’ = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD.

Pages 921-930
María Llorens-Martin, Cátia M. Teixeira, Almudena Fuster-Matanzo, Jerónimo Jurado-Arjona, Víctor Borrell, Eduardo Soriano, Jesús Avila, Félix Hernández (Handling Associate Editor: Khalid Iqbal)
Tau Isoform with Three Microtubule Binding Domains is a Marker of New Axons Generated from the Subgranular Zone in the Hippocampal Dentate Gyrus: Implications for Alzheimer’s Disease
Abstract: In the adult hippocampal dentate gyrus, newborn granule cells grow dendrites into the molecular layer and send axons into the CA3 region. Several molecular markers have been used to analyze production of these new neurons; however, no good markers for new axons have been described. Here we demonstrate that tau protein isoform with three microtubule binding domains (3R-Tau) is a marker of those axons following an antigen retrieval protocol. By using retrovirus-mediated GFP transduction, GFP can be detected in a period of 7-14 days after viral infection. We also provide a "proof of principle" demonstration of the power of that labeling showing modulation of 3R-Tau positive axons under physiological conditions (exercise and aging) as well as in a FTDP-17 neurodegenerative model and Alzheimer’s disease models (mice overexpressing AβPPsw,ind or GSK3β). We conclude that 3R-Tau would be an efficient marker and a valuable tool to study new axons in adult neurogenesis as well as in neurodegenerative processes.