Journal of Alzheimer's Disease - Volume 24, issue 3

Authors: Johansson, Per | Mattsson, Niklas | Hansson, Oskar | Wallin, Anders | Johansson, Jan-Ove | Andreasson, Ulf | Zetterberg, Henrik | Blennow, Kaj | Svensson, Johan

Article Type: Research Article

Abstract: The cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ)1-42 , T-tau, and P-tau have good diagnostic accuracy for clinically diagnosed Alzheimer's disease (AD). However, in multi-center studies, the predictive values of the CSF biomarkers have been lower, possibly due to differences in procedures for lumbar puncture and CSF handling and storage, and to differences in patient populations, clinical evaluations, and diagnostic procedures. Here we investigate the diagnostic accuracy of CSF biomarkers in a well defined homogeneous mono-center population. We also evaluate an extended panel of amyloid related biomarkers. Sixty consecutive patients admitted for cognitive impairment to a memory clinic were recruited. The …participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 32), patients with stable MCI (n = 13), patients with other dementias diagnosed at primary evaluation or upon follow-up (n = 15), and healthy controls (n = 20). CSF was analyzed for Aβ1-42 , T-tau, P-tau, AβX-38 , AβX-40 , AβX-42 , sAβPPα, and sAβPPβ. In multivariate analysis, the core biomarkers Aβ1-42 , T-tau, and P-tau demonstrated a high ability to diagnose AD versus the combined groups of controls and stable MCI, with an area under the receiver operating characteristic curve (AUROC) of 0.97 (95% CI 0.93–1.00, p < 0.0001). The additional biomarkers only marginally increased AUROC to 0.98 (95% CI 0.95–1.00, p < 0.0001), this increase mainly mediated by AβX-42 . In conclusion, CSF biomarkers Aβ1-42 , T-tau, and P-tau have very high diagnostic accuracy in a well defined cohort of untreated patients, demonstrating the excellent potency of CSF biomarkers to identify pathological processes in AD when a stringent analytical protocol is used. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, cerebrospinal fluid, diagnosis

DOI: 10.3233/JAD-2011-101878

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 537-546, 2011

Authors: Scheff, Stephen W. | Price, Douglas A. | Schmitt, Frederick A. | Scheff, Melissa A. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a slowly progressing form of dementia characterized in its earliest stages as a loss of memory. Individuals with amnestic mild cognitive impairment (aMCI) may be in the earliest stages of the disease and represent an opportunity to identify pathological changes related to the progression of AD. Synaptic loss is one of the hallmarks of AD and associated with cognitive impairment. The inferior temporal gyrus plays an important role in verbal fluency, a cognitive function affected early in the onset of AD. Unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina …3 of the inferior temporal gyrus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI had significantly fewer synapses (36%) compared to individuals with no cognitive impairment. Individuals with AD showed a loss of synapses very similar to the aMCI cohort. Synaptic numbers correlated highly with Mini Mental State Examination scores and a test of category verbal fluency. These results demonstrate that the inferior temporal gyrus is affected during the prodromal stage of the disease and may underlie some of the early AD-related clinical dysfunctions. Show more

Keywords: Dementia, language, synapses, verbal fluency

DOI: 10.3233/JAD-2011-101782

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 547-557, 2011

Authors: Marengoni, Alessandra | Fratiglioni, Laura | Bandinelli, Stefania | Ferrucci, Luigi

Article Type: Research Article

Abstract: Thousand and twelve dementia-free elderly (60–98 years old) enrolled in the InChianti Study (Italy) were evaluated at baseline (1998–2000) and at 3-year follow-up (2001–2003) with the aim of analyzing the association of lifetime socioeconomic status (SES) with prevalent and incident cognitive impairment no-dementia (CIND). SES was defined from information on formal education, longest held occupation, and financial conditions through life. CIND was defined as age-adjusted Mini-Mental State Examination score one standard deviation below the baseline mean score of participants without dementia. Logistic regression and Cox proportional-hazards models were used to estimate the association of SES with CIND. Demographics, occupation characteristics …(i.e., job stress and physical demand), cardiovascular diseases, diabetes, apolipoprotein E (APOE) genotype, smoking, alcohol consumption, depressive symptoms, and C-reactive protein were considered potential confounders. Prevalence of CIND was 17.7%. In the fully adjusted model, low education (OR = 2.1; 95% confidence intervals, CI = 1.4 to 3.2) was associated with prevalent CIND. Incidence rate of CIND was 66.0 per 1000 person-years. Low education (HR = 1.7; 95% CI = 1.04 to 2.6) and manual occupation (HR = 1.9; 95% CI = 1.0 to 3.6) were associated with incident CIND. Among covariates, high job-related physical demand was associated with both prevalent and incident CIND (OR = 1.6; 95% CI = 1.1 to 2.4 and HR = 1.5; 95% CI = 1.0 to 2.3). After stratification for education, manual occupation was still associated with CIND among participants with high education (HR = 2.2; 95% CI = 1.2 to 4.3 versus HR = 1.4; 95% CI = 0.2 to 10.4 among those with low education). Proxy markers of lifetime SES (low education, manual occupation and high physical demand) are cross-sectional correlates of CIND and predict incident CIND over a three-year follow-up. Show more

Keywords: Cognitive impairment no-dementia, epidemiology, education, finances, occupation, socioeconomic status

DOI: 10.3233/JAD-2011-101863

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 559-568, 2011

Authors: Antonini, Vuokko | Marrazzo, Agostino | Kleiner, Giulio | Coradazzi, Marino | Ronsisvalle, Simone | Prezzavento, Orazio | Ronsisvalle, Giuseppe | Leanza, Giampiero

Article Type: Research Article

Abstract: Sigma-1 receptor agonists have recently attracted much attention as potential therapeutic drugs for cognitive and affective disorders, however, it is still unclear whether they act via modulation of transmitter release or activation of sigma-1 receptors in memory-related brain regions. In the present study, we have investigated the anti-amnesic and neuroprotective actions of the compound (-)-methyl (1S,2R)-2-{[1-adamantyl(methyl)amino]methyl}-1-phenylcyclopropane-carboxylate) [(-)-MR22], a selective sigma-1 receptor agonist able to protect cultured cortical neurons from amyloid toxicity. To this aim, cognitive deficits, cholinergic loss, and amyloid peptide accumulation were obtained in the rat by simultaneous injections of a selective immunotoxin and pre-aggregated amyloid peptide into the …basal forebrain and the hippocampus, respectively. At about five–six weeks post-lesion, the double-lesioned animals exhibited dramatic deficits in spatial learning and memory, whereas animals with single injections of either compound were not or only marginally affected, in spite of equally severe cholinergic loss or amyloid deposition. Administration of (-)-MR22 appeared to reverse cognitive impairments in double lesioned animals, whereas pre-treatment with the selective sigma-1 antagonist BD1047 abolished this effect. Moreover, (-)-MR22 normalized the levels of cell-associated amyloid-β protein precursor (AβPP) in the neocortex and hippocampus, thus sustaining a non-amyloidogenic AβPP processing. By contrast, treatment with (-)-MR22 produced no effects whatsoever in intact animals. Thus, sigma-1 receptor agonists such as (-)-MR22 may ameliorate perturbed cognitive abilities and exert a protective action onto target neurons, holding promises as viable tools for memory enhancement and neuroprotection. Show more

Keywords: Acetylcholine, Alzheimer's disease, amyloid, animal model, immunotoxin, sigma-1 receptor agonist, spatial learning, rat

DOI: 10.3233/JAD-2011-101794

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 569-586, 2011

Authors: Belbin, Olivia | Brown, Kristelle | Shi, Hui | Medway, Christopher | Abraham, Richard | Passmore, Peter | Mann, David | Smith, A. David | Holmes, Clive | McGuinness, Bernadette | Craig, David | Warden, Donald | Heun, Reinhard | Kölsch, Heike | Love, Seth | Kalsheker, Noor | Williams, Julie | Owen, Michael J. | Carrasquillo, Minerva | Younkin, Steven | Morgan, Kevin | Kehoe, Patrick G.

Article Type: Research Article

Abstract: A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association …with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies. Show more

Keywords: Alzheimer's disease, angiotensin-1 converting enzyme, haplotype, heterogeneity, late onset, meta-analysis

DOI: 10.3233/JAD-2011-101914

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 587-597, 2011

Authors: Bloudek, Lisa M. | Spackman, D. Eldon | Veenstra, David L. | Sullivan, Sean D.

Article Type: Research Article

Abstract: Cholinesterase inhibitors and memantine are medications used in the treatment of Alzheimer's disease (AD). These agents have been shown to reduce the rate of AD progression in randomized trials. The objective of this study is to evaluate the association between treatment with cholinesterase inhibitors or memantine and the probability of transitioning to a more severe Clinical Dementia Rating (CDR) state. Analysis was limited to possible or probable AD patients from NACC-UDS with three or more observations, baseline CDR score of 0.5 or 1, and without reported use AD drugs at enrollment. Use of an AD drug at any observation after …baseline was classified as treatment. Odds of CDR stage were calculated by multinomial logistic regression controlling for baseline age, baseline MMSE score, education, marital status, race, gender, place of residence, and time since last measure. The resulting coefficients from logistic regression were used to calculate transitional probabilities. A total of 1,114 patients were included. No differences were observed in the probability of transitioning to more severe CDR states based on treatment, but treated patients had lower odds of death, OR 0.49 (95% CI 0.31 to 0.79) compared to untreated. Ultimately, this study failed to detect a difference in the probability of progressing to a more severe AD state as a result of treatment in an observational cohort of AD patients, but is limited by non-randomized treatment selection and small dataset. The NACC-UDS dataset is ongoing and this analysis may be improved if repeated when more data is available. Show more

Keywords: Alzheimer's disease, disease progression, drug therapy, economic, models, probability

DOI: 10.3233/JAD-2011-101758

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 599-607, 2011

Authors: Lerner, Alan Jay

Article Type: Book Review

DOI: 10.3233/JAD-2011-110003

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 609-609, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-101759

Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 611-613, 2011