Home Advances for a New Century Advertising
About JAD Alzheimer Award Recommend JAD
Editorial Board Press Releases Feedback
For Authors Subscriptions Search
Contents/Abstracts Related Links Letters to Editor


an IOS Press publication


 PDFs of all articles are available from IOS Press. 

F O R   A U T H O R S




















The Journal of Alzheimer's Disease is published by IOS Press. 1998-2012 Journal of Alzheimer's Disease

JAD - Volume 23, Number 4

Volume 23, Number 4, March 2011

Pages 567-598
Lucija Tomljenovic (Handling Associate Editor: Christopher Exley)
Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?
Abstract: The brain is a highly compartmentalized organ exceptionally susceptible to accumulation of metabolic errors. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of the elderly and is characterized by regional specificity of neural aberrations associated with higher cognitive functions. Aluminum (Al) is the most abundant neurotoxic metal on earth, widely bioavailable to humans and repeatedly shown to accumulate in AD-susceptible neuronal foci. In spite of this, the role of Al in AD has been heavily disputed based on the following claims: 1) bioavailable Al cannot enter the brain in sufficient amounts to cause damage, 2) excess Al is efficiently excreted from the body, and 3) Al accumulation in neurons is a consequence rather than a cause of neuronal loss.  Research, however, reveals that: 1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, 2) Al sequesters different transport mechanisms to actively traverse brain barriers, 3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and 4) since 1911, experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. Misconceptions about Al bioavailability may have mislead scientists regarding the significance of Al in the pathogenesis of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence and should not be dismissed. Immediate steps should be taken to lessen human exposure to Al, which may be the single most aggravating and avoidable factor related to AD.

Pages 599-605
William A Banks, Vijaya B. Kumar, Susan A. Farr, Ryota Nakaoke, Sandra M. Robinson, John E. Morley
Impairments in Brain-to-Blood Transport of Amyloid-β and Reabsorption of Cerebrospinal Fluid in an Animal Model of Alzheimer’s Disease are Reversed by Antisense Directed Against Amyloid-β Protein Precursor
Abstract: The blood-brain barrier (BBB) influences brain levels of amyloid-β (Aβ) by transporting Aβ out of the brain (efflux) and by the reabsorption of cerebrospinal fluid (CSF) into the blood stream (bulk flow).  In Alzheimer’s disease (AD) and normal aging, unknown factors impair Aβ efflux and bulk flow in aging and in AD.  These impairments have been proposed as mechanisms by which the Aβ burden in brain can increase.  Impairment in Aβ efflux occurs in animal models of AD, including the aged SAMP8 mouse.  Here, we show that CSF reabsorption is also reduced by about 50% in SAMP8 mice (p<0.05).  We then determined whether an antisense directed at the Aβ region of the amyloid-β protein precursor (AβPP) and previously shown to decrease brain levels of AβPP and to reverse the cognitive impairments of the SAMP8 mouse was able to reverse these impairments.  We found that the antisense restored both the CSF reabsorption, more than doubling the rate of efflux, and the saturable efflux of Aβ.  These findings suggest that AβPP/Aβ itself contributes to the impairments in bulk flow and saturable efflux of Aβ and that reduction of AβPP/Aβ levels can restore normal function of the BBB.

Pages 607-615
Rebecca P. Gelber, Helen Petrovitch, Kamal H. Masaki, G. Webster Ross, Lon R. White
Coffee Intake in Midlife and Risk of Dementia and its Neuropathologic Correlates
Abstract: While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent.  We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965-1968) examined for dementia in 1991-1993, including 418 decedents (1992-2004) who underwent brain autopsy.  Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline.  Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer’s disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake.  Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347.  There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types.  However, men in the highest quartile of caffeine intake (>277.5 mg/d) were less likely than men in the lowest quartile (≤115.5 mg) to have any of the lesion types (adjusted-OR, 0.45; 95%CI, 0.23-0.89; p, trend=0.04).  Coffee and caffeine intake in midlife were not associated with cognitive impairment, dementia, or individual neuropathologic lesions, although higher caffeine intake was associated with a lower odds of having any of the lesion types at autopsy.

Pages 617-627
Wei Qian, Xiaomin Yin, Wen Hu, Jianhua Shi, Jianlan Gu, Inge Grundke-Iqbal, Khalid Iqbal, Cheng-Xin Gong, Fei Liu (Handling Associate Editor: Jin-Jing Pei)
Activation of Protein Phosphatase 2B and Hyperphosphorylation of Tau in Alzheimer’s Disease
Abstract: Protein phosphatase 2B (PP2B) is one of the major brain phosphatases and can dephosphorylate tau at several phosphorylation sites in vitro.  Previous studies that measured PP2B activity in human brain crude extracts showed that PP2B activity was either unchanged or decreased in Alzheimer’s disease (AD) brain. These results led to the speculation that PP2B might regulate tau phosphorylation and that a down-regulation of PP2B might contribute to abnormal hyperphosphorylation of tau.  In this study, we immunoprecipitated PP2B from brains of six AD subjects and seven postmortem- and age-matched controls and then measured the phosphatase activity.  We found a three-fold increase in PP2B activity in AD brain as compared with control brains.  The activation was due to the partial cleavage of PP2B by calpain I that was activated in AD brain.  The truncation of PP2B appeared to alter its intracellular distribution in the brain. In human brains, PP2B activity correlated positively, rather than negatively, to the levels of tau phosphorylation at several sites that can be dephosphorylated by PP2B in vitro. Truncation of PP2B in the frontal cortex was more than in the temporal cortex, and tau phosphorylation was also more in the frontal cortex. Taken together, these results indicate that truncation of PP2B by calpain I elevates its activity but does not counteract the abnormal hyperphosphorylation tau in AD brain.

Pages 629-639
Kebreten F. Manaye, Joanne S. Allard, Sara Kalifa, Amy C. Drew, Guang Xu, Donald K. Ingram, Rafael de Cabo, Peter R. Mouton (Handling Associate Editor: Gemma Casadesus)
17α-Estradiol Attenuates Neuron Loss in Ovariectomized Dtg AβPP/PS1 Mice
Abstract: Quantitative microanalysis of brains from patients with Alzheimer’s disease (AD) find neuronal loss and neuroinflammation in structures that control cognitive function. Though historically difficult to recapitulate in experimental models, several groups have recently reported that by middle-age, transgenic mice that co-express high levels of two AD-associated mutations, amyloid-β protein precursor (AβPPswe) and presenilin 1 (PS1ΔE9), undergo significant AD-type neuron loss in sub-cortical nuclei with heavy catecholaminergic projections to the hippocampal formation. Here we report that by 13 mos of age these dtg AβPPswe/PS1ΔE9 mice also show significant loss of pyramidal neuron in a critical region for learning and memory, the CA1 subregion of hippocampus, as a direct function of amyloid-β (Aβ) aggregation. We used these mice to test whether 17α-estradiol (17αE2), a less feminizing and non-carcinogenic enantiomer of 17β-estradiol, protects against this CA1 neuron loss. Female dtg AβPPswe/PS1ΔE9 mice were ovariectomized at 8-9 months of age and treated for 60 days with either 17αE2 or placebo via subcutaneous pellets. Computerized stereology revealed that 17αE2 ameliorated the loss of neurons in CA1 and reduced microglial activation in the hippocampus. These findings support the view that 17αE2, which may act through non-genomic mechanisms independent of traditional estrogen receptors, could prevent or delay the progression of AD in older men and women.

Pages 641-654
Lei Zhu, Jianchun Yu, Qiaoqiao Shi, Wenwen Lu, Bin Liu, Shaofeng Xu, Ling Wang, Jingxian Han, Xiaoliang Wang (Handling Associate Editor: Jianzhi Wang)
Strain- and age-related alteration of proteins in the brain of SAMP8 and SAMR1 mice
Abstract: In order to discover and identify the key protein biomarkers in the aging process, we performed a differential proteomic analysis of hippocampus and cortex in 5- and 15-month old senescence-accelerated mouse prone 8 (SAMP8) as well as in control strain SAM/resistant 1 (SAMR1). Using 2-DE combined with MALDI TOF/TOF mass spectrometry, about 1700 protein spots were isolated, and three groups of differentially expressed proteins were identified. The first group contained the strain-specific and non-age-related differential proteins that were differentially expressed in SAMP8 compared with SAMR1 mice. The changes might be implicated in the genetic difference between SAMP8 and SAMR1 mice; specifically, the proteins ubiquitin carboxyl- terminal esterase L3, mitofilin, adenylate kinase 4, and an unnamed protein product (gi|12847201). The proteins in the second group were age-specific, which were differentially expressed between 5- and 15-month old SAM mice. Those proteins are particularly interesting since the changes were aging-related and some of them were previously reported to be expressed in Alzheimer’s disease patients. These proteins included N-myc downstream regulated gene 2, enolase 2, Cu/Zn superoxide dismutase, myosin, and two unnamed protein products (gi|74214304 and gi|74178239). The protein in the third group was SAMP8 specific-age-related protein, which was identified as heme binding protein 1. The present study provides new information about SAMP8 specific and aging-related protein changes in brain. Further investigations will be performed to reveal the significance of these proteins in brain aging process and the potential roles as biomarkers for effective diagnosis and therapy.

Pages 655-664
Henry Ka-Fung Mak, Zhipeng Zhang, Kelvin Kai-Wing Yau, Linda Zhang, Queenie Chan, Leung-Wing Chu
Efficacy of voxel-based morphometry with DARTEL and standard registration as imaging biomarkers in Alzheimer's disease patients and cognitively normal older adults at 3.0 Tesla MR Imaging
Abstract: Quantitative MRI of the hippocampus has been increasingly employed as a biomarker in Alzheimer’s disease (AD). We compare voxel-based morphometry (VBM) standard and DARTEL registration with manual hippocampal volumetry in AD patients and cognitively normal older adults. Participants were 20 cognitively normal elderly subjects and 19 AD patients who met the criteria of probable AD according to NINCDS-ADRDA. Bilateral manual hippocampal volumetry was conducted alongside VBM of hippocampal regions-of-interest (ROIs) generated with standard and DARTEL registration using hippocampal masks and total intracranial volume normalization. All normalized hippocampal measurements showed significant reduction (20-30%; p<0.001) in AD compared to controls. Logistic regression analysis also showed significant effects (odds ratios ranged from 88.2% to 94.0%) of all normalized measurements in predicting AD incidence after adjusting for age, gender, and education. The overall prediction accuracies of manual RH and LH volumes, standard RH-ROI and LH-ROI VBM, DARTEL RH-ROI, and LH-ROI VBM were 87.2%, 84.6%, 87.2%, 76.9%, 87.2%, and 87.2%, respectively. As imaging biomarkers, VBM with DARTEL and standard registration have similarly high efficacies as manual hippocampal volumetry in discriminating AD from cognitively normal elderly adults.

Pages 665-671
Robert M. Brouillette, Corby K. Martin, John B. Correa, Allison B. Davis, Hongmei Han, William D. Johnson,  Heather C. Foil, Aimee Hymel, Jeffrey N. Keller
Memory For Names Test Provides A Useful Confrontational Naming Task For Aging and Continuum of Dementia
Abstract: There is an increasing need to develop new neuropsychometric tools sensitive enough to detect subtle declines in cognitive performance during normal aging, as well as to distinguish between normal aging and the earliest stages of dementia.  In this study, we report our findings regarding a new confrontational naming test, the Memory for Names test.  We conducted evaluations utilizing a cohort of 234 elderly participants who comprised a spectrum of cognitive function ranging from normal for age (Uniform Data Set Overall Appraisal = 2, Clinical Dementia Rating = 0) to demented (Clinical Dementia Rating = 1-2, Mini Mental Status Examination Total Score <25).  The Memory for Names test was found to measure the same cognitive construct as the Boston Naming Test.  In conclusion, the Memory for Names test is a reliable and valid measure of age-related cognitive function that can discriminate between normal aging and mild cognitive impairment, and between mild cognitive impairment and dementia.

Pages 673-687
Magdalena E. Cuevas, Henny Haensgen, Fernando J. Sepúlveda, Gabriela Zegers, Jorge Roa, Carlos Opazo, Luis G. Aguayo
Soluble Aβ1-40 peptide increases excitatory neurotransmission and induces epileptiform activity in hippocampal neurons
Abstract: It is believed that amyloid-β peptide (Aβ), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer’s disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble Aβ1-40 on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of Aβ1-40 peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of Aβ were time and concentration dependent and were accompanied by increases in glutamatergic (0.8 ± 0.2 Hz to 2.9 ± 0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA- and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either Aβ or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro-convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of Aβ1-40 participates in the regulation of synaptic transmission increasing excitability and producing a pre epileptogenic state in hippocampal neurons.

Pages 689-699
Mark E. Orcholski, Qiang Zhang, Dale E. Bredesen
Signaling Via Amyloid Precursor-Like Proteins APLP1 and APLP2
Abstract: The amyloid-β protein precursor (AβPP) has been implicated in Alzheimer’s disease (AD) not only as a precursor of the amyloid-β peptide but also as a mediator of signal transduction. We recently identified novel mediators of AβPP signaling via interactions with Mint/X11 family proteins Mint1 and Mint3. These mediators include transcriptional co-activators Taz and Yap. Here we show that Taz and Yap also mediate signaling via the AβPP paralogues APLP1 and APLP2 through interactions with Mint1 and Mint3. APLP1 and APLP2 formed transcriptionally active triple protein complexes with the adaptor protein Mint3 and each of the transcriptional regulators Taz and Yap, and complex formation was regulated by the γ-secretase cleavage of APLP1 and APLP2. The presence of Mint1 instead of Mint3 in the complex prevented its translocation to the nucleus. APLP1 displayed much lower transactivation levels compared to AβPP and APLP2. These results indicate that all three AβPP family members are capable of activating gene transcription via Mint3-Taz and Mint3-Yap.

Pages 701-707
Eliana Venturelli, Chiara Villa, Chiara Fenoglio, Francesca Clerici, Alessandra Marcone, Luisa Benussi, Roberta Ghidoni, Salvatore Gallone, Francesca Cortini, Maria Serpente, Claudia Cantoni, Giorgio Fumagalli, Elisa Ridolfi, Stefano Cappa, Giuliano Binetti, Massimo Franceschi, Innocenzo Rainero, Maria Teresa Giordana, Claudio Mariani, Nereo Bresolin, Elio Scarpini, Daniela Galimberti
BAG1 is a protective factor for sporadic Frontotemporal Lobar Degeneration but not for Alzheimer’s disease
Abstract: BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor that interacts with tau and regulates its proteasomal degradation. A significant increase of the BAG-1M isoform was found in Alzheimer’s disease (AD) brains, and the protein co-localized with tau and amyloid. We carried out an association study of BAG1 in a population of 291 patients clinically diagnosed with frontotemporal lobar degeneration (FTLD), none of whom was a carrier of mutations in progranulin or microtubule associated protein tau genes and 374 with AD as compared with 314 age- and gender-matched controls. In addition, another candidate named Chromatin-modifying protein 5 (CHMP5) and located in the same linkage disequilibrium block, has been included in this study. The distribution of the two single nucleotide polymorphism (SNPs), rs844239 in CHMP5 and rs706118 in BAG1, covering 100% gene variability, were determined. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD as compared with controls (16.7 versus 23.9%; p=0.007, OR: 0.35, CI: 0.25-0.50), whereas allelic frequency of the SNP in patients with AD was similar to controls (24.3%, p>0.05). Conversely, no significant association was found as regards CHMP5 rs844239. Stratifying according to gender, no differences were observed. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD, suggesting its specific role in a pathogenic event in FTLD. Nevertheless, a replication study would be needed to confirm these preliminary results.

Pages 709-716
Ramit Ravona-Springer, Michal Schnaider Beeri, Uri Goldbourt
Exposure to the Holocaust and World War II Concentration Camps during Late Adolescence and Adulthood is not Associated with Increased Risk for Dementia at Old Age
Abstract: Holocaust and Nazi concentration camp survivors were subjects to prolonged and multi-dimensional trauma and stress. The aim of the present study was to assess the association between exposure to such trauma during late adolescence and adulthood with dementia at old age. In 1963, approximately 10,000 male civil servants aged 40-71 participated in the Israel Ischemic Heart Disease (IIHD) study. Of them, 691 reported having survived Nazi concentration camps [concentration Camp Survivors (CCS)].  Additional 2316 participants were holocaust survivors but not concentration camp survivors (HSNCC) and 1688 were born in European countries but not exposed to the Holocaust (NH). Dementia was assessed in 1999-2000, over three decades later, in 1889 survivors of the original IIHD cohort; 139 of whom were CCS, 435 were HSNCC, and 236 were NH. Dementia prevalence was 11.5% in CCS, 12.6% in HSNCC, and 15.7% in NH. The odds ratio of dementia prevalence, estimated by age adjusted logistic regression, for CCS as compared to HSNCC was 0.97 (95% CI, 0.53-1.77), approximate Z=-0.10; p=0.92. Further adjustment for socioeconomic status, diabetes mellitus, and other co-morbidity at midlife (coronary heart disease, lung, and kidney disease), and height did not change the results substantially. Thus, in subjects who survived until old age, late adolescence and adulthood exposure to extreme stress, as reflected by experiencing holocaust and Nazi concentration camps, was not associated with increased prevalence of dementia. Individuals who survived concentration camps and then lived into old age may carry survival advantages that are associated with protection from dementia and mortality.

Pages 717-726
Daniela Varges, Klaus Jung, Joanna Gawinecka, Uta Heinemann, Matthias Schmitz, Nicolas von Ahsen, Anna Krasnianski, Victor W. Armstrong, Inga Zerr
Amyloid-β 1-42 Levels are Modified by Apolipoprotein E ε4 in Creutzfeldt-Jakob Disease in a Similar Manner as in Alzheimer’s disease
Abstract: The presence of apolipoprotein E (ApoE) ε4 allele is a risk factor for Alzheimer’s disease (AD) and associated with a more pronounced reduction of amyloid-β 1-42 (Aβ1-42) in the cerebrospinal fluid (CSF). Because a decrease of Aβ1-42 and increase of tau protein levels, both important biomarkers for AD, are also reported in Creutzfeldt-Jakob disease (CJD), we analyzed if a similar relationship can be observed in this rapid progressive dementia. Our study included 309 patients with sporadic CJD (147 neuropathologically confirmed and 162 probable cases). We analyzed the role of ApoE ε4 in sporadic CJD (sCJD), in particular the influence on the CSF-markers 14-3-3 protein, tau protein, neuron-specific enolase, S100 protein, Aβ1-42, and Aβ1-40. No differences in the ApoE ε4 allele frequency and ApoE genotype distribution between sCJD and published healthy controls were observed. The ApoE ε4 allele had no effect on disease duration or age at onset. We detected a dose-dependent ApoE ε4 effect on the decrease of Aβ1-42 in sCJD. ApoE ε4 carriers with one ApoE ε4 allele showed significantly reduced Aβ1-42 values (p<0.0001) in comparison with non-carriers. ApoE ε4 allele is not a risk factor for sCJD but modifies the Aβ1-42 levels in CSF in a similar manner as in AD. Based on our results in sCJD patients, we hypothesize that the ApoE ε4 effect on Aβ1-42 values might not be disease-specific.

Pages 727-735
Julián Benito-León, Elan D. Louis, Alex J. Mitchell, Félix Bermejo-Pareja
Elderly-onset essential tremor and mild cognitive impairment: A population-based study (NEDICES)
Abstract: Mild cognitive impairment (MCI) is often considered to be a transitional stage between normal aging and dementia. Frontal-executive dysfunction, memory impairments, and dementia have been associated with essential tremor (ET). Yet the association between MCI and ET has only been examined in one prior study. We determined whether ET is associated with MCI. We identified all persons with MCI and ET in a dementia-free, population-based study in central Spain (NEDICES). MCI was diagnosed using consensus criteria of the International Working Group on MCI. Forty-two (20.3%) of 207 ET cases had MCI versus 399 (16.1%) of 2,472 non-ET subjects (controls) (odds ratio [OR] = 1.32, 95% Confidence Interval [CI] = 0.93 to 1.89, p = 0.12). In a model that adjusted for age, gender, educational level, smoking, hearing impairment, depressive symptoms or antidepressant use, and use of a medication that could potentially affect cognitive function, the OR was 1.28, 95% CI = 0.88 to 1.84, p = 0.19. In an adjusted model, ET cases with tremor onset after age 65 were 57% more likely to have MCI than controls (OR = 1.57, 95% CI = 1.03 to 2.38, p = 0.03), whereas ET cases with tremor onset prior to age 65 and controls were equally likely to have MCI (OR = 0.73, 95% CI = 0.34 to 1.57, p = 0.43). In this study, older-onset ET was associated with MCI. This finding supports the hypothesis that cognitive disturbances are one of the core non-motor symptoms of ET.

Pages 737-747
Jimmy F.P. Berbée*, Tim Vanmierlo*, Karlygash Abildayeva, Arjan Blokland, Paula J. Jansen, Dieter Lütjohann, Thomas Gautier, Eric Sijbrands, Jos Prickaerts, M’hamed Hadfoune, Frans C.S. Ramaekers, Folkert Kuipers, Patrick C.N. Rensen, Monique Mulder * Authors contributed equally
Apolipoprotein CI Knock-Out Mice Display Impaired Memory Functions
Abstract: The ε4 allele of apolipoprotein E (APOE4), which is a well established genetic risk factor for development of Alzheimer’s disease (AD), is in genetic disequilibrium with the H2 allele of apolipoprotein C1 (APOC1), giving rise to increased expression of apoC-I. This raises the possibility that the H2 allele of APOC1, either alone or in combination with APOE4, provides a major risk factor for AD. In line herewith, we previously showed that mice overexpressing human APOC1 display impaired learning and memory functions. Here, we tested the hypothesis that the absence of Apoc1 expression in mice may improve memory functions. In contrast with our expectations, Apoc1-/- mice showed impaired hippocampal-dependent memory functions, as judged from their performance in the object recognition task (p<0.001) as compared to their wild-type littermates. No gross changes in brain morphology or in brain sterol concentrations were detected in knockout mice compared to wild-type littermates. Apoc1 deficiency reduced the expression of ApoE mRNA (-25%, p<0.05), but not ApoE protein levels. In line with a role for apoC-I in inflammatory processes, we observed significantly increased mRNA concentrations of the proinflammatory marker tumor necrosis factor α and oxidative stress related heme oxygenase 1 (Hmox1) in the absence of glial activation. In conclusion, the absence of ApoC-I results in impaired memory functions, which is, together with previous data, suggestive of an important, bell-shaped gene-dose dependent role for ApoC-I in appropriate brain functioning. The relative contributions of the H2 allele of APOC1 and/or APOE4 in the risk assessment in AD remain to be determined.

Pages 749-759
Martine Vercelletto, Claire Boutoleau-Bretonnière, Christelle Volteau, Michèle Puel, Sophie Auriacombe, Marie Sarazin, Bernard-François Michel, Philippe Couratier, Catherine Thomas-Antérion, Patrice Verpillat, Audrey Gabelle, Véronique Golfier, Evelyne Cerato, Lucette Lacomblez
Memantine in Behavioral Variant Frontotemporal Dementia: negative results
Abstract: We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC–Plus (Clinician’s Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI),  Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19–30). On the CIBIC–Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0. 4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of scorebetween the memantine group and the placebo group [(MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10)] except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated.This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.