Journal of Alzheimer's Disease - Volume 23, issue 4

Authors: Venturelli, Eliana | Villa, Chiara | Fenoglio, Chiara | Clerici, Francesca | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Gallone, Salvatore | Cortini, Francesca | Serpente, Maria | Cantoni, Claudia | Fumagalli, Giorgio | Ridolfi, Elisa | Cappa, Stefano | Binetti, Giuliano | Franceschi, Massimo | Rainero, Innocenzo | Giordana, Maria Teresa | Mariani, Claudio | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, BAG1, CHMP5, frontotemporal lobar degeneration, neurodegeneration, polymorphism, risk factor

DOI: 10.3233/JAD-2010-101416

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 701-707, 2011

Authors: Ravona-Springer, Ramit | Beeri, Michal Schnaider | Goldbourt, Uri

Article Type: Research Article

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. Show more

Keywords: Adolescence, adulthood, dementia, Holocaust, Nazi concentration camps

DOI: 10.3233/JAD-2010-101327

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 709-716, 2011

Authors: Varges, Daniela | Jung, Klaus | Gawinecka, Joanna | Heinemann, Uta | Schmitz, Matthias | von Ahsen, Nicolas | Krasnianski, Anna | Armstrong, Victor W. | Zerr, Inga

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoprotein E, codon 129 genotype, Creutzfeldt-Jakob disease, dementia, prion, tau

DOI: 10.3233/JAD-2010-101527

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 717-726, 2011

Authors: Benito-León, Julián | Louis, Elan D. | Mitchell, Alex J. | Bermejo-Pareja, Félix

Article Type: Research Article

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. Show more

Keywords: Elderly, epidemiology, essential tremor, mild cognitive impairment

DOI: 10.3233/JAD-2011-101572

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 727-735, 2011

Authors: Berbée, Jimmy F.P. | Vanmierlo, Tim | Abildayeva, Karlygash | Blokland, Arjan | Jansen, Paula J. | Lütjohann, Dieter | Gautier, Thomas | Sijbrands, Eric | Prickaerts, Jos | Hadfoune, M'hamed | Ramaekers, Frans C.S. | Kuipers, Folkert | Rensen, Patrick C.N. | Mulder, Monique

Article Type: Research Article

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. Show more

Keywords: APOC1, apolipoprotein C-I, cholesterol, cognition and brain, memory

DOI: 10.3233/JAD-2010-100576

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 737-747, 2011

Authors: Vercelletto, Martine | Boutoleau-Bretonnière, Claire | Volteau, Christelle | Puel, Michèle | Auriacombe, Sophie | Sarazin, Marie | Michel, Bernard-François | Couratier, Philippe | Thomas-Antérion, Catherine | Verpillat, Patrice | Gabelle, Audrey | Golfier, Véronique | Cerato, Evelyne | Lacomblez, Lucette

Article Type: Research Article

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 score between 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. Show more

Keywords: Behavioral variant frontotemporal dementia, double-blind placebo-controlled trial, memantine

DOI: 10.3233/JAD-2010-101632

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 749-759, 2011

Article Type: Correction

DOI: 10.3233/JAD-2010-001435

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 761-761, 2011

Article Type: Correction

DOI: 10.3233/JAD-2010-001436

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 763-763, 2011

Article Type: Other

DOI: 10.3233/JAD-2010-101633

Citation: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 765-767, 2011